Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403

Contents lists available at ScienceDirect

Journal of Photochemistry and Photobiology C:

Photochemistry Reviews
journal homepage: www.elsevier.com/locate/jphotochemrev

How does the skin sense sun light? An integrative view of light
sensing molecules
Leonardo Vinicius Monteiro de Assis a,1,3 , Paulo Newton Tonolli b,1 ,
Maria Nathalia Moraes c , Maurício S. Baptista d,∗,2 , Ana Maria de Lauro Castrucci a,e,2
a
Department of Physiology, Institute of Biosciences, University of São Paulo, Brazil
b
Human Genome and Stem Cell Research Center, Institute of Biosciences, University of Sao Paulo, Brazil
c
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil
d
Department of Biochemistry, Institute of Chemistry, University of São Paulo, Brazil
e
Department of Biology, University of Virginia, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: The consensus on the effects of excessive sun exposure on human health has long emphasized the negative
Received 3 October 2020 effects of solar UV radiation. Nevertheless, although UV radiation has been demonized, less is known about
Received in revised form 2 February 2021 the consequences of sun exposure while using sunscreen, which can lead to high visible light exposure. UV
Accepted 18 February 2021
and visible light play key roles in vitamin D synthesis, reduction of blood pressure, among other beneficial
Available online 22 February 2021
effects. In this review, we aim to provide a comprehensive view of the wide range of responses of the
human skin to sunlight by revisiting data on the beneficial and harmful effects of UV and visible light.
Keywords:
We start by exploring the interaction of photons in the skin at several levels including physical (depth of
Skin biology
UV radiation
photon penetration), chemical (light absorption and subsequent photochemical events), and biological
Visible light (how cells and tissues respond). Skin responses to sun exposure can only be comprehensively understood
Chromophores through a consideration of the light-absorbing molecules present in the skin, especially the light-sensing
Opsins proteins called opsins. Indeed, many of the cellular responses to sun exposure are modulated by opsins,
Photosensors which act as the “eyes of the skin”.
© 2021 Elsevier B.V. All rights reserved.

Contents

1. Sunlight: friend or foe? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2. Overview of skin biology and exposome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. Upon absorption light photons generate excited states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4. How visible light and UV radiation interact with opsins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4.1. Discovery of the opsins in the skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4.2. Photophysical properties of opsins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.3. Advancement in the field: a historical view of opsin functions in the skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4.3.1. UVR sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4.3.2. Visible light sensor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

∗ Corresponding author at: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Avenida Prof. Lineu Prestes 748, São Paulo, SP, 05508-000, Brazil.
E-mail address: baptista@iq.usp.br (M.S. Baptista).
1
Both authors had same contribution to this study and share the 1st authorship.
2
Both authors had same contribution to this study and share the senior authorship.
3
Current address: Institute of Neurobiology, Center for Brain, Behavior, and Metabolism, University of Lübeck, Germany.

https://doi.org/10.1016/j.jphotochemrev.2021.100403
1389-5567/© 2021 Elsevier B.V. All rights reserved.
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
Leonardo Monteiro de Assis holds a Bpharm (Federal
University of Ouro Preto, 2014) and a PhD in Physiol-
ogy (University of São Paulo, USP, 2019). During his PhD
and postdoctoral experience, Leonardo and his research
group in a pioneering fashion characterized the pho-
toreception (opsins) and temporal controlling systems
(clock genes) in normal and malignant melanocytes. Cur-
rently, Leonardo is a research associate at the University
of Lübeck, Germany.
Paulo Newton Tonolli is a biologist graduated from the
Federal University of Sao Carlos (Brazil) and currently is a
researcher scientist in the Human Genome and Stem Cell
Research Center at University of Sao Paulo (USP), Brazil.
He received his Ph.D. degree in Sciences (Biochemistry)
from the Institute of Chemistry at USP, investigating the
effects of visible light on the skin keratinocytes, focus-
ing on the photosensitization of endogenous molecules
and organelles and photodamage. His Master degree was
studying mitochondrial DNA (mtDNA) repair and the role
of transcription factor A in the defense of mtDNA against
oxidative stress.
Maria Nathalia Moraes has a major in Biological Sci-
ences by CES/JF, M.Sc. and PhD. in Physiology by the
University of Sao Paulo. She worked in Dr. Castrucci’s
lab for 12 years, where she studied the circadian clock
and opsins in non-mammalian and mammalian verte-
brate models. She elucidated how light and temperature
is translated as a synchronizer factor in peripheral tissues
and which triggered signaling pathways ultimately lead to
clock gene modulation. During her post-doctoral position,
she demonstrated for the first time, a link between TRP
channels and clock genes in the modulation of mammalian
peripheral tissues related with energy metabolism. Cur-
rently, she holds a young research investigator position in
Dr. Cipolla-Neto’s lab, focusing her investigation on the effects of chronodisruption
on the central nervous system and metabolic tissues, using animals that sponta-
neously develop glaucoma. Her main question is related to what are the short and
long-term consequences of the lack of light exposure on health.
Mauricio S. Baptista PhD is professor of Biochem-
istry at the University of São Paulo (USP, Brazil). He
earned Bachelor (1990) and Master (1992) degrees in
Biochemistry from USP and holds a doctoral degree
(1996) in Chemistry from Marquette University (USA).
He did his post-doctoral training at UW-Madison (1997)
and was visiting professor (2006) at the Université
Joseph Fourier (Grenoble-France). His main interests
are photochemistry/photobiology, membranes/interfaces
and mechanisms of cell death, where he published over
180 papers. He serves as co-editor in chief of J. Photochem
Photobiol. B and J.Photochem.Photobiol. (Elsevier) and is part
of the board of Photochemical & Photobiological Sciences
(RSC) and of Scientific Reports (Nature). He is a member of the The Academy of
Sciences of the State of São Paulo.
Ana Maria de Lauro Castrucci graduated in Biology and
got her Master and PhD degrees in Physiology at the Uni-
versity of Sao Paulo. Her post doctorate was made under
the supervision of Prof Mac Eugene Hadley, at the Uni-
versity of Arizona, during the 80’s. In 1999, she took a
sabbatical leave of one year as a visiting scholar at the
Uniformed Services University of the Health Sciences,
Maryland. Since 2005 she has collaborated with the Uni-
versity of Virginia. She retired in 2001 from the University
of São Paulo as Full Professor of Physiology, but kept her
laboratory as Senior Professor, since then. She is a member
of the Brazilian Academy of Sciences and of The Academy
of Sciences of the State of São Paulo and received the
National Order of Scientific Merit awarded by the President of Brazil. She presently
holds research grants from the São Paulo Research Foundation, FAPESP, focusing the
following subjects: clock genes, opsins, light, temperature, endocrines and signaling
mechanisms in crustaceans, fish, amphibians, birds and mammals.
2
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
1. Sunlight: friend or foe?
Unquestionably, spending excessive periods of time in the
sun is harmful to the skin and overall health. Current photo-
protection strategies mainly focus on avoiding exposure to the
ultra-violet portion of the sun spectra (UV, 200–400 nm). However,
the overwhelming focus on the harm of UV radiation neglects three
important aspects of sun-skin interactions: i. While UV has been
proven to be carcinogenic [1], there is no scientific evidence indi-
cating that only UV is dangerous to the skin; ii. A solid body of
evidence has highlighted the danger of excessive exposure to non-
UV wavelengths of light [2]; iii. Sunbathing also has many beneficial
effects [2,3].
The American Academy of Dermatology has encouraged peo-
ple to use UV protection on a daily basis, with a zero-tolerance
approach to sun exposure [1,3,4]. Many professional societies have
endorsed similar views, promoting campaigns that are consistently
centered on the negative effects of sunlight, though their pre-
scriptions vary in the recommended level of sun avoidance. These
campaigns have prompted unrestricted sunscreen usage, disre-
garding the many good effects of sun exposure on human health
in the right amounts.
In addition, users are often unaware that the sunscreens do
not block all wavelengths of sunlight, including those marketed as
offering “broad-spectrum protection” [5,6]. These sunscreens actu-
ally only offer meaningful protection against UVB (280–320 nm)
and UVA (320–400 nm) radiation, which only represent around 2%
of the solar irradiance that reaches the Earth’s surface, leading to
a false sense of protection. It is not surprising that epidemiological
studies have reported a worldwide increase in the incidence of skin
cancer [1,4], despite the rising use of sunscreen [5]. While a num-
ber of factors are behind this trend, the usual explanation tends
to be superficial, with claims that people do not correctly apply
sunscreen on the skin, frequently spreading just 25–30 % of the
recommended sunscreen amount [3]. However, many researchers
have concluded that the current photoprotection guidelines are
ineffective because they lack a scientific basis and ignore a large
body of evidence reported in literature [2,6–8].
The redness in the skin caused by sun exposure, also called ery-
thema or sunburn, arises mainly from the effect of UVB radiation,
although UVA and visible light also cause skin redness with lesser
intensity [2]. Skin erythema is an acute inflammatory response to
damage which is concentrated in the nuclear DNA of skin cells.
The redness functions as a warning sign to get out of the sun. All
people have this response, though it is smaller and more difficult
to measure in people with darker skin tones [9]. Sunscreens avoid
this response by blocking UVB rays. Even so, using sunscreen does
not prevent a darkening of the skin, which many find aesthetically
pleasing. This, too, is a natural protective mechanism to defend
the skin against excessive sun exposure [10]. Current sunscreen
technology does not provide any protection against ∼98 % of the
solar irradiance, which is comprised of visible light and infrared
radiation (IR). Photons in the visible and IR ranges interact with
the skin, culminating in a burst of free radicals in the skin [11].
Remarkably, visible light and a portion of IR called infrared A (IRA,
760–1440 nm) radiation penetrate much deeper in the skin than
UV rays (Fig. 1, Table 1). Thus, individuals using UV protection will
nevertheless suffer from the action of visible light and infrared radi-
ation, which generate reactive oxidants and can saturate the skin’s
redox defenses [2,11–13]. Within the skin, melanocytes sense blue
light and UVA radiation through opsins (Fig. 1) and trigger melano-
genesis [14,15]. A number of other questions which have not yet
been properly answered will be also noted below.
Another misconception is that darker-skinned people are fully
protected from the sun. Melanin is a natural pigment that does
defend the skin against DNA damage, redness and carcinogenesis
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al. Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403

Fig. 1. A) Solar radiation and its different wavelengths exert several effects on the skin. UV radiation is subdivided into UVC, which is fully blocked by the atmosphere, UVB,
and UVA radiation. Upon contact with the skin tissue, light photons can be reflected or diffusely transmitted at the surface. As light photons penetrate deeper into the skin,
the following outcomes may take place: 1) photons may be diffusely reflected; 2) photons may penetrate the skin layers (directly transmitted light), which is dependent
on the wavelength (see panel B for better visualization); 3) photons may be dissipated as heat energy. B) Skin layers, cell types and appendices are represented. Opsins are
expressed in keratinocytes, melanocytes, and fibroblasts. Chromophores are found in the epidermis and dermis. The depth of UV radiation and light penetration in the skin is
shown (please refer to Table 1 and Fig. 3). Opsins and chromophores represent two venues for UV and light photons interaction, which may lead to physiological responses.
The reader is referred to the text and to the Graphical Abstract for more details on each biological process mediated by these photosensors. Figure created by the authors.

Table 1 reaching the skin per second by square centimeter of an exposed

Penetration of particular wavelength ranges of light into the skin. Infrared B (IRB,
area. Around 98 % (UV) of the photons reaching the skin are filtered
1440 – 3000 nm) and C (IRC, 3000 nm – 10000 nm) only interact with the first lay-
ers of the epidermis, thus showing a poor penetration capacity. Data values were or reflected by the sunscreen, while the remaining of sunlight pho-
approximate due to different techniques and methodologies and were based on tons will interact with the skin without any protection barrier [22]
[62,65,66]. (Fig. 1). This person will not show signs of sunburn and may even
Wavelength (nm) Tissue Penetration (mm)
get a “beautiful tan”, but he/she is not warned that the usual tanning
is triggered by damage in the skin.
300 < 0.5
The sun protection factor (SPF) is not a precise parameter to
350 0.8
400 1 ensure comprehensive skin protection from sunlight. The light
450 1.5 sources used to calculate SPF and to evaluate UVA protection only
500 2.5 expose people to UV. The design of these tests is therefore not
550 3
indicative of real-world conditions and may give consumers a false
600 4
650 4.5 sense of protection, since these tests do not measure the full effect
700 5.2 of solar radiation. Additionally, SPF calculations do not consider
750 5.5 the photoinduced generation of reactive oxidants and the resulting
Near Infrared (750–1400) > 5.5 oxidative stress [22]. Indeed, antioxidant compounds (e.g., vitamins
C and E) have been studied by the Baptista group and others, and
the inclusion of these compounds in sunscreen formulations has
from UVB radiation [16]. However, as demonstrated by Baptista’s improved photoprotection [22–24]. In any case, it is undeniable
group, melanin acts as a double-edged sword, since it also induces that a person sunbathing on the beach and correctly using com-
oxidative stress and indirect DNA lesions such as the premuta- mercially available sunscreen will not be protected against 98 % of
genic 8-oxo-dG when skin and hair are exposed to visible light and the photons that will come into contact with their skin [25] (Fig. 1).
UVA [17–19]. Thus, even though individuals with more melanin Even though such a sunbather will not show signs of sunburn and
can spend more time in the sun without noticeable acute effects may even get a beautiful tan, they will likely be unaware of the skin
in the skin, they are not immune from the chronic effects of sun damage caused by their tanning. Could ineffective photoprotection,
exposure. While their thicker dermis makes wrinkles less notice- then, be the reason for increasing levels of skin cancer cases? Many
able, people with dark skin are more vulnerable to depigmentation scientists are working to shed light on this question [6,8,18,26–28].
[20]. Even so, a much greater problem for Asian and African people Furthermore, currently available sunscreens have been shown
in temperate climates is increased rates of cardio-metabolic dis- to suffer from several drawbacks. Many of them contain organic
eases that appear to be partly due to inadequate sunlight exposure molecules that have been shown to be toxic to skin, such as oxy-
and, consequently, low levels of vitamin D production [21] (see benzone [29]. The Food and Drug Administration (FDA) in the
additional information below). Therefore, darker-skinned people US has requested more data on the safety of twelve compounds
should also be encouraged to get some unprotected sun exposure, found in sunscreen formulations: ensulizole, octisalate, homos-
though always avoiding excesses. alate, octocrylene, octinoxate, oxybenzone, avobenzone, cinoxate,
Now, imagine someone sunbathing on the beach and using dioxybenzone, meradimate, padimate O, and sulisobenzone [30].
correctly the present marketed sunscreens. During this time, this The negative effects of sunscreens may also include widespread
individual will receive billions and billions of photons from sunlight damage to the environment. It is estimated that 14,000 tons of sun-

3
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
screens enter the oceans annually, from beachgoers and domestic
sewage effluent [31]. Recent studies have shown that organic com-
pounds in sunscreens may be involved with bleaching and death
of coral reefs [31,32]. States like Hawaii (SB 2571, Act 104, March
3rd, 2018) with its famous barrier reefs have prohibited the use of
sunscreen with formulations that include oxybenzone [33].
Discussions of skin protections often neglect the benefits of sun
exposure for human health. Approximately 90 % of all vitamin D
used in our body is formed through the action of UVB rays on
the skin, where vitamin D3 synthesis takes place [34]. Vitamin D
plays a substantial function in regulating calcium and phospho-
rus levels, improving bone and muscle health, strengthening the
immune system, and preventing several types of cancer, cardio-
vascular diseases, depression and other illnesses [35–38]. While
estimates vary on the optimal time to spend in the sun, popula-
tion studies show that people with fair skin, in temperate regions,
should spend around 10−20 min sunbathing three times per week
with their full body exposed [38]. In contrast, the trend towards
spending one’s time largely indoors and not exposing oneself to
sunlight without protection has resulted in an epidemic of vita-
min D deficiency [34–40]. In the US, the treatment of diseases
caused by vitamin D deficiency costs around US$ 16–25 billion,
while the cost of skin cancer treatments amounts to US$ 8 billion
[41,42].
Largely missing in the discourse around sun exposure is a
discussion of its beneficial effects beyond vitamin D synthesis.
Understanding these effects is perhaps the most important con-
tribution of this review. Skin cells such as keratinocytes and
melanocytes can detect the presence of sunlight using a set of pro-
teins called opsins, which are responsible for capturing light in
photoreceptive organs such as the eyes [43] (Fig. 1). These proteins
will be discussed further elsewhere in this review, but for now it is
enough to mention that it is intriguing that sunlight photoreception
by skin triggers various physiological responses, such as melanin
production [14,15,44]. Indeed, it even regulates the cell activity of
the immune system [45]. The body’s central biological clock, the
suprachiasmatic nucleus located in the hypothalamus, adjusts itself
each day using sun light [46,47], while disruptions to this rhythm
can have negative health effects [47,48]. Low sun exposure can also
exacerbate conditions such as obesity and cardiovascular disease
[49]. Another important benefit of sun exposure is related to blood
pressure levels. Weller’s group has suggested that 20 min of sun
exposure can lower blood pressure for hours [50]. Solar radiation
activates the production of nitric oxide, a potent vasodilator, which
lowers blood pressure [51]. This may explain the higher incidence
of cardiovascular disease at higher latitudes than in the tropics [52].
Exposure to visible light appears to stimulate an opsin that mod-
ulates the activity of subcutaneous white adipose tissue cells, the
main fat deposit in humans [53]. In addition, a study conducted by
Lindqvist between 1990 and 2010 with 30,000 women indicated
that the average lifespan of women with regular sun exposure was
two years longer than those who did not receive much sunlight
[54]. Furthermore, sun-avoiding women had higher risks of heart
problems, autoimmune diseases, and diabetes.
These results highlight the urgent need for a novel photoprotec-
tion paradigm that considers the benefits of moderate sun exposure
without sunscreen usage beyond the positive effects of vitamin
D. Moderate sunbathing with no sunscreen has many benefits
for human welfare and health, and may even provide protection
against skin cancer.
In order to understand the diverse and contradictory effects of
skin exposure to sunlight, we need to start considering how light
interacts with skin. In particular, we will pay special attention to the
reactions induced by light when absorbed by endogenous photo-
sensitizers and the consequences of the photosensitized oxidation
reactions for biomolecules and cells. We will also comprehensively
4
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
describe and discuss the interaction of opsin receptors with UV and
visible light.
Our goal in this review is to provide a global analysis of how
the skin senses light of different wavelengths through interactions
with chromophores and light- sensing molecules named opsins.
We also examine the way in which the skin influences peripheral
organs after receiving light stimuli. Crucially, our approach deals
with the skin as an important part of a complex system, with a sig-
nificant role due to its photosensitivity. We aim to provide a global
view of how the skin senses light and UV radiation. Notably, we
seek to determine whether chromophores or opsins are the pre-
dominantly responsible for skin photosensitivity, which has been
a leading investigation by scientists in this area. We further call for
a reevaluation of skin’s sensory ability and its impact in skin phys-
iopathology. Finally, we highlight important gaps in the literature
and suggest future directions in the skin photobiology field.
2. Overview of skin biology and exposome
The skin is the human body’s largest organ and the first
defensive barrier. In addition to its protective function, skin is
sensitive to touch, pain, pressure, itching, temperature, and solar
radiation [55]. The skin is comprised of two layers, the epidermis
and dermis, which contain a number of cell types. The epidermis is
largely comprised of keratinocytes, which originate in epidermal
stem cells. These cells migrate upwards and differentiate into the
various layers of the outer skin: from the base to surface, these
are the stratum basale, stratum spinosum, stratum granulosum,
stratum lucidum, and stratum corneum. As they migrate upwards,
keratinocytes start to express different markers and proteins that
ultimately generate the epidermal barrier [55]. Melanin-producing
cells named melanocytes reside in the stratum basale. Melanin
synthesis is stimulated in response to interaction with light and
the pigment is transferred to neighboring keratinocytes, where
it acts as a shield against UV radiation and a scavenger of free
radicals [56–58]. The dermis provides support and nourishment
to the epidermis and is mainly comprised of fibroblasts, lymph
and blood vessels, nerve endings, hair follicles, and glands. This
layer is subdivided into two sections: the papillary layer, which
has nerve endings and capillaries, and the reticular layer, which
is mainly composed of collagen and elastic fibers [55] (Fig. 1). The
hypodermis was long considered to be part of the skin, though
it is currently viewed as part of a subcutaneous tissue with an
important influence on skin biology [59,60].
Several environmental factors pose a threat to skin physiology.
In an important publication, Passeron’s group identified several
harmful factors for skin and coined the term “skin exposome”. The
following factors are currently known to affect the biology of the
skin: 1) solar radiation (UV and infrared radiation, visible light),
2) air pollution, 3) tobacco smoke, 4) nutrition, 5) miscellaneous
factors which have not been as thoroughly studied, such as stress,
sleep deprivation, temperature, and cosmetics [61].
Of these factors, this review will focus primarily on the effects
of UV radiation and visible light on the skin. UV radiation is
classified into UVC (100–280 nm), UVB (280–320 nm), and UVA
(320–400 nm) (Fig. 2). These definitions were constructed at the
turn of the 20th century though their classification has little to
do with skin photobiology [58]. Since energy is inversely propor-
tional to the wavelength, UVC has the highest energy, followed by
UVB and UVA [57]. The skin penetration capacity of UV radiation is
directly proportional to its wavelength: UVB reaches only the epi-
dermis and UVA reaches the dermis (Fig. 3, Table 1) [62–64]. The
UV radiation that reaches the Earth comprises only 2 % of the total
solar radiation reaching the surface, of which UVA and UVB repre-
sent approximately 90–95 % and 5–10 %, respectively, while UVC is
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al. Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403

Fig. 2. A. Spectrum of solar irradiance reaching the surface of the Earth: ultraviolet radiation UVB (200 – 320 nm) and UVA (320 – 400 nm), visible light (400 – 750 nm), and
infrared radiation (750 – 2500 nm). B. Absorption of mammalian opsins and main skin endogenous photosensitizers and biomolecules. Black line represents the range of
photon absorption through the electronic transition, which takes place when electrons are excited to a higher energy level, and red line by vibrational transition (starting at
750 nm). Figure created by the authors.

Fig. 3. Penetration of different fractions of sunlight in the human skin. Image taken from [104] under the terms of creative commons.

5
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
completely blocked by the ozone layer [63,64]. In this review, we
will use the abbreviation UVR when discussing studies that utilize
both UVA and UVB emission devices.
The link between chronic UVR exposure and skin cancer is well
documented in the literature [2]. The effects of UV radiation on
the skin include: I) sunburn, caused mainly by UVB [63,64]; II)
damage to nuclear and mitochondrial DNA resulting in the accu-
mulation of cyclobutane pyrimidine dimers and 6–4 photoproducts
(UVB mainly), and of 8-oxoguanine (8-oxoG) due to the indirect
action of UVA [63,67,68]; III) DNA repair, which may trigger apo-
ptosis, resulting in skin shedding [64,69]; IV) generation of reactive
species of oxygen and nitrogen (ROS and RNS), which damage lipids
and membranes [64,67,69]; V) activation of a complex neuroen-
docrine system in the skin with likely systemic effects [70,71];
VI) pre-vitamin D3 generation as a result of 7- dehydrocholes-
terol conversion by UVB [72]; VII) increased ␣-MSH production
that leads to immediate and delayed pigmentary responses [58];
VIII) degradation of cellular matrix by metalloproteinases which is
associated with skin aging [62]; IX) immunosuppression associated
with decreased immunosurveillance [58,63,64,67].
Visible light (400–750 nm) comprises approximately half of the
total solar irradiance reaching the Earth’s surface and is represented
by several wavelengths, which penetrate the skin to different
extents, with longer wavelengths penetrating deeper. Visible light
is comprised of the following shades, listed in decreasing order of
wavelength and skin penetration: red light (625–740 nm), orange
(590–625 nm), yellow (565–590 nm), green (500–565 nm), blue
(450–485 nm), and violet (400–450 nm) (Table 1, Fig. 3) [65,66].
Blue light is one of the most studied visible light wavelengths
and it has been implicated in the proliferation and differentia-
tion of human cells, as well as in the increased oxidative stress
of keratinocytes [73], systemic release of ␤-endorphin [71], and
hair follicle growth in ex vivo [74]. In murine models, blue light
elicits an anti-inflammatory response [75], apoptosis of melanoma
cells [76], and vasorelaxation [77]. Violet light has been shown to
downregulate markers of human keratinocyte differentiation [78].
Other wavelengths, such as green light, display anti-inflammatory
effects on rats [79] and a stimulatory activity on angiogenesis and
myofibroblast differentiation in a rat model of burn injury [80]. Yel-
low light has been shown to inhibit melanogenesis and to induce
autophagy in human melanocytes [81]. Red light, the farthest-
reaching wavelength of the visible light spectrum, has been shown
to enhance DNA repair activity [82] and proliferation [83,84]. A
growing body of literature has documented the role of visible light
in deleterious effects that may contribute and/or lead to skin can-
cer [7,8,62]. However, a link between visible light exposure and skin
cancer remains controversial. This debate is of major importance
to public health, since the majority of sunscreens do not protect
against visible light. Meanwhile, an exciting and fast-growing field
named photobiomodulation, which uses low-intensity lasers, has
shown that light stimulation under controlled conditions improves
several human disorders and diseases (reviewed in [85,86]). How-
ever, photobiomodulation applications in medical routines have
been delayed due to the lack of standard procedures and protocols
in both basic and clinical studies [85,87].
Upon stimulation by UV radiation and/or visible light, several
complex biological mechanisms are activated in order to sustain
skin homeostasis. It is beyond the scope of this review to explore
such mechanisms, though it bears mentioning that skin’s defensive
responses to solar radiation include the following mechanisms: I) a
local neuroendocrine system with a systemic effect [56,88,89]; II) a
melanin-producing system that protects cells against the effects of
direct and indirect UV radiation [56,57]; III) apoptosis of severely
damaged cells [90–92]; IV) DNA repair [93]; V) anti-oxidative stress
system [92,94,95]; VI) the molecular clock, which acts as a tem-
poral controller of the above-mentioned systems, aligning several
6
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
Table 2
Absorption and reflection at different wavelength ranges from UV to near infrared.
Photon absorption was determined by [105,106]. Values for reflection, scatter-
ing, and thermal dissipation (represented in Fig. 1) were generated by subtracting
absorption values from 1.
Wavelength (nm) Absorption Reflection
/scattering/thermal
energy dissipation
UVB (280–320) 0.1 0.9
UVA1 (340–400) 0.3 0.7
UVA2 (320–340) 0.2 0.8
Blue (450–480) 0.8 0.2
Green, Yellow, Orange (500–625) 0.7 0.3
Red (625–750) 0.6 0.4
Near Infrared (750–1400) 0.5 0.5
biological parameters with the external environment in a time-
coordinated fashion [96–98].
3. Upon absorption light photons generate excited states
The sun emits a broad spectrum of electromagnetic radiation
that includes gamma rays, ultraviolet radiation, and visible light
(the maximum intensity of solar radiation occurs at wavelengths of
around 500 nm), as well as infrared, microwaves, and radio waves.
However, a major part of this radiation does not reach the Earth’s
surface. The main reason is that the Earth is protected by its mag-
netic field, the ozone layer, and by other atmospheric properties
that restrict the penetration of electromagnetic radiation [99]. The
ozone layer absorbs radiation below 280 nm, meaning that only
UVA and UVB, visible, and infrared radiation (IRA, 760–1440 nm;
IRB, 1440–3000 nm, and IRC 3000 nm–10000 nm) will come into
contact with human skin. As mentioned above, UV comprises only
∼2 % of the solar radiation that reaches the Earth’s surface (Fig. 2).
Most of the mutagenic activity of UV radiation is due to UVB pho-
tons being absorbed directly by DNA molecules. However, most of
the photons that reach the skin are in the visible (∼47 %) and IR
(∼51 %) ranges (Fig. 2).
It is important to note that the effect of solar radiation on skin
depends on how photons interact with skin molecules. Especially
relevant is the process called electronic excitation, which occurs
when a molecule absorbs a photon and is raised from a low-lying
electronic state (called ground state) to another electronic state of
higher energy, and the specific characteristics (lifetime and reac-
tivity) of the created excited state. Note that both UV radiation
and visible light induce electronic transitions (Fig. 2), though they
differ in terms of the molecules they interact with and the exact
characteristics of the excited states they bring about. The impor-
tant question to answer is whether these transient excited states
react during their short lifetime and with which molecule. One
should also consider that photons from the different regions of the
sun radiation spectrum will have completely different penetration
depth in the skin (Fig. 3).
A number of processes prevent photons from penetrating the
skin. These include reflection, scattering, and absorption (Fig. 1,
Table 2) [100,101]. Note that UV and most IR radiation does
not penetrate deep into the skin (Table 1) [102]. UVB radiation
barely reaches the basal layer and UVA radiation penetrates a few
micrometers into the dermis, while IRB and IRC only reach the
first molecular layers of the epidermis (Table 1). Most IR is effi-
ciently absorbed by O H and C H bonds and quickly transformed
into heat. Photons in the visible and IRA ranges penetrate most
deeply into the skin because photons in this wavelength region
are neither scattered nor absorbed effectively, spreading through-
out the dermis and even reaching the hypodermis (Tables 1 and 2,
Fig. 3), resulting in a wide range of interactions with these tissues
[103,104]. Thus, the penetration depth of photons is a determin-
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
ing factor in the range of molecules and the consequent biological
effects on the skin.
The popularity of measures to avoid UV radiation via sunscreen
use is based on an understanding that UV photons are mutagenic
and carcinogenic. However, one should always remember that the
photons are not mutagenic by themselves, instead, photons par-
ticipate of photochemical reactions by raising molecules to their
excited states that chemically react with other molecules. We will
discuss the specific interactions between UV photons and skin in
greater detail below. Importantly, the exclusive focus on the role of
UV radiation has resulted in an inadvertent conception of photons
in the visible regions as being safe for the skin, which is not borne
out by scientific observations.
Many decades ago, Leff and Krinsky [107] demonstrated that
red light photons (∼610 nm) are mutagenic to microalgae (Euglena
gracilis). This is because the chlorophyll molecules in microalgae
absorb light at this wavelength. The same question posed to explain
the mutagenic effect of UV radiation can be repeated here: how
can visible light in the red spectral region be mutagenic? As men-
tioned above, it all depends on the absorbing molecules and the
type of excited states that are formed, more than on the energy of
the photon itself. Chlorophyll molecules engage in photosensitized
oxidation reactions upon absorption of photons at certain wave-
lengths. Humans do not have chlorophyll in the skin and indeed
red light seems to be safe for us [85,87], but the concept of red
light being safe, just because it has less energy than UV, falls to the
ground. The simple and precise explanation is that red light is safe
for us because we do not have chlorophyll in our skin. However, we
do have several other molecules that can engage in photosensitized
oxidation reactions (see further discussion below).
Reactions of the excited states can be grouped into two main
types. Direct events are purely photochemical, with molecules
in excited states reacting among themselves or with neighbor-
ing molecules, while indirect photosensitization events involve
the absorbing molecules (called photosensitizers), forming excited
states that exchange energy or electrons with neighboring
molecules and usually returning to the ground state. As mentioned
above, sunlight photons of different wavelength regions will inter-
act with different molecules located in distinct subcellular niches
defining their biological effects (Fig. 2). Photons with lower wave-
lengths (and higher energy) will interact with a larger number of
molecules. For example, UVB photons interact with a myriad of
molecules (proteins, nucleic acids, lipids), including the genetic
material of living cells, located mainly in the basal layer and the
upper layers of the dermis. Upon absorbing a photon, the nitroge-
nous bases of the DNA in these cells are brought into an excited
state. Most of these excited states quickly return the absorbed
energy as heat, fully replenishing their respective ground state
species. However, a small fraction of these events will favor the
formation of excited states that will engage in a direct photochemi-
cal reaction called a cycloaddition reaction. Cycloaddition reactions
occur when a photon excites a deoxythymidine that is in molecular
contact with another deoxythymidine, forming either cyclobutane
pyrimidine dimers (CPDs) or, to a lesser extent, pyrimidine (6-4)
pyrimidone photoproducts (6-4PPs) (Fig. 4). These adducts distort
the DNA double helix, unwinding and kinking it, affecting the inter-
action with transcription factors, replication, transcription, and
DNA repair. If the damage is not recognized and repaired by DNA-
repairing enzymes, it can be maintained in the DNA, where it leads
to mutations.
The acute effect of these DNA alterations is a strong inflamma-
tory response also known as sunburn, in which the skin becomes
reddish and painful to touch. UVB radiation is also known to cause
long-term effects including a transition mutation in dipyrimidine
sequences containing cytosine, especially at 5"-TCG and 5"-CCG
[108]. These mutations occur more frequently in some specific
7
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
Fig. 4. Formation of pyrimidine dimers (cyclobutane pyrimidine dimers and (6-4)
photoproducts) in adjacent pyrimidines in DNA during exposure to UV, especially
UVB. Image obtained from [112] under the terms of creative commons.
regions in the genome (hotspots), such as the CpG islands and
methylated CpG sequences (where 5-methylcytosine is deami-
nated to thymine), where they cause transition mutations of C to
T, 5-methylcytosine to T, and CC to TT [108,109]. The CpG islands
(sequences with 1 kb, on average, and rich in G + C) are usually
found at the promoter region of some tumor suppressor genes
such as TP53, which is why these mutations are commonly asso-
ciated with skin cancer [110]. According to Pfeifer and colleagues,
in human skin cancers, about 35 % of all mutations in the p53 gene
are transitions at 5"-TCG and 5"-CCG [108].
Note that all of this is not a consequence of the intrinsic and
isolated properties of UVB photons, but instead is a consequence of
the absorption of UVB photons by nucleic acids. Although all nucle-
obases (adenine, cytosine, guanine, and uridine) can absorb UVB,
only a few excitation events will lead to photoproducts [111,112].
AS mentioned above, an electronically excited pyrimidine adjacent
to another pyrimidine will react to form either a CPDs or a 6-4 PPs
(Fig. 4) [111,112]. In other words, the photon needs to be absorbed
by the pyrimidine base in order to induce the mutagenesis. The
mutagenic effect of visible light in microalgae occurs in an anal-
ogous fashion [107]. In this case, the absorbing molecules are not
DNA, but instead chlorophyll, a photosynthetic pigment present in
the microalgae. The induced reaction is not a direct cycloaddition
between adjacent pyrimidine dimers, but instead, is a photosensi-
tized oxidation reaction, which occurs due to the formation of an
excited state after the absorption of photons (Fig. 5).
Photosensitizers (PS) depend on light absorption at the proper
wavelength to allow the formation of excited states, which are
intrinsically more reactive than ground states. During their tran-
sient lifetimes, the duration of which depends on the radiative
and non-radiative deactivation routes, numerous reactions can
occur. Usually, the initial excited state formed after light absorp-
tion is a singlet excited state (PS(S1)), with a lifetime measured
in nanoseconds (Fig. 5). Consequently, PS(S1) do not generally
result in diffusion-dependent reactions unless these are generated
in physical contact with the reactant [113] or when reactants are
present at high concentrations. Triplet excited states (PS(T1)) usu-
ally live much longer than PS(S1) and are therefore key elements
of photosensitized oxidation reactions. PS(T1) are typically formed
by intersystem crossing (spin inversion in the excited state) from
the PS(S1), but can also be formed by the suppression of PS(S1)
excited states by molecular oxygen or by an energy transfer process
from other photosensitizers present in the molecular surroundings
(Fig. 5).
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al. Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403

Fig. 5. Mechanisms of photosensitized oxidation reactions involving the molecular oxygen (O2 ). The photosensitizer (PS) is a molecule capable to absorb light depending on
its specific absorption spectra. Once excited, the PS goes from its ground state PS(S0) to its singlet excited PS(S1), and through a process called intersystem crossing forms
triplet excited PS(T1) states. Other mechanisms can also form triplet species, like suppression of singlet excited state by ground state oxygen and energy transfer from other
photosensitizers. Both PS(S1) and PS(T1) can react directly with biomolecules, like carbohydrates, lipids, proteins or nucleic acids, via Type I contact-dependent reaction,
resulting in formation of radicals, like PS, capable to initiate other radical chain reactions. Photosensitizers can work as electron donors or acceptors, but in the scheme, we
only show the PS working as a photo-oxidant (electron acceptor). PS· (an anion radical derived from the PS) can react with oxygen forming anion radical super oxide (O2 .− ).
Generation of O2 .- can also occur by the direct electron donation from PS(S1) and PS(T1) to O2 (these pathways are not shown in the scheme). Since triplets live much longer
than singlets, triplets are the main agent to cause biological oxidation. Otherwise, PS (T1) can react with molecular oxygen 3 O2 , via the Type II reaction, generating singlet
• •
oxygen (1 O2 ). Both of these diffusive oxidant species (1 O2, O2 − ) will affect the redox homeostasis of cells and tissues but 1 O2, is much more reactive than O2 − [114]. Figure
taken from [114] with permission.

There are two main mechanisms of photosensitized oxida- Table 3

Relevant endogenous photosensitizers with their respective wavelength range of
tions, termed type I and type II, and PS(T1) are significant to both
light absorption (␭ range) and efficiency of singlet oxygen generation (S).
mechanisms. Type I reactions depend on the encounter of the
excited-state species with biological substrates. These reactions Molecule ␭ range (nm) S [reference]
usually start with an electron or hydrogen abstraction, leading to Pro-vitaminD2 270−280 0.8 [119]
radical chain reactions. Excited states are stronger oxidizing and Vitamin D3 270−280 0.2 [120]
reducing agents and both PS(S1) and PS(T1) can behave as elec- Vitamin B-12 320−380; 450−600 0.2 [121]
All-trans retinal 400−600 0.6 [122]
tron donors and acceptors. In the scheme of Fig. 5 we only mention
All-trans retinol 400−600 0.8 [123]
the direct photo-induced oxidations by both PS(S1) and PS(T1), Riboflavin 300−500 0.5 [124]
meaning that these species accept an electron from a biological FMN 300−500 0.6 [125]
substrate and form the one-electron reduced radical derived from MiniSOG (LOV) 300−500 0.03 [125]
SOPP (LOV) 300−500 0.19 [125]
the PS. We do not mention the possibility of photo-induced reduc-
Pterin 200−400 0.18 [126]
tions, in which both PS(S1) and PS(T1) donate an electron to oxygen Folic acid 200−400 < 0.02 [126]
to form the anion radical superoxide (O2 .-). Although there are Thymine 230−300 0.07 [127]
other species that could receive an electron from PS(S1) and PS(T1), Uracil 230−300 0.13 [127]
molecular oxygen is the most obvious one for thermodynamic and Adenine 230−280 0.03 [127]
Cytosine 230−300 0.02 [127]
kinetic reasons [114]. It is worth mentioning that these pathways
Phenylalanine 200−280 0.06 [128]
are usually not as prevalent as the type II reactions and O2 .- is not Tyrosine 200−300 0.17 [128]
as reactive as 1 O2 [114]. Tryptophan 200−320 0.06 [128]
Type II refers to the energy transfer reaction from the PS triplet BSA 200−320 0.04 [128]
Bacteriochlorophyll a 300−800 0.61 [129]
state to molecular oxygen (3 O2 ), generating singlet oxygen (1 O2 )
Bacteriochlorophyll b 300−800 0.68 [129]
(Fig. 5). This is the most prevalent oxidative pathway for molecules Bacteriopheophytin a 300−800 0.69 [129]
that form PS(T1), since PS(S1) is short-lived and the energy transfer Bacteriopheophytin b 300−800 0.61 [129]
reaction between PS(T1) and oxygen is usually diffusion-limited, Reaction Center 300−800 0.03 [130]
while the formation of PS(T1) by an electron transfer to oxygen is a R. sphaeroides
Lipofuscin 300−500 ∼0.1 [131]
minor product [114]. 1 O2 is a strong oxidant and can add to the dou-
Melanin 300−800 ∼0.02 [17]
ble bond of lipids, proteins, and nucleic acids, starting peroxidation Urocanic 200−320 ∼0 [116]
reactions [114]. As shown by Baptista’s group, irreversible biolog-
ical damage occurs with the abstraction of a hydrogen from the
double bonds of biomolecules [114,115]. In addition, they suggest which is much more difficult to be directly evaluated, especially in
that the fact that the irreversible damage occurs due to contact- biological systems. Since 1 O2 is formed when triplets are generated
dependent reactions indicates that the damage can be confined in the presence of oxygen the yield of singlet oxygen defines a min-
within a nanometric location from the PS [115]. imum limit for the yield of triplets and indicates that a molecule is
As described above, the formation of a triplet excited state is a PS.
key to triggering the photosensitized oxidation reactions. But, are Importantly, Table 3 demonstrates that 1 O2 generation is the
there relevant photosensitizers in the skin that can form triplets rule rather than the exception for PS molecules. Basically, it is very
upon light absorption? There is plenty [116,117]. Table 3 provides difficult to generate an excited state completely avoiding triplet
an overview of the range of wavelengths absorbed by important generation. Note that several amino acids and nitrogenous bases
biological molecules that are present in the skin and the yield of are efficient photosensitizers. Vitamins, in general, generate triplets
singlet oxygen generation. Besides being one of the oxidant species efficiently, meaning that these molecules are effective in caus-
that cause the photosensitized oxidative damage, 1 O2 generation ing photooxidative damage. Indeed, vitamins are the main species
can also be used to report the presence of triplet excited states, responsible for the photooxidative damage induced by UVA, caus-

8
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
Fig. 6. Families of opsins and the corresponding coupled G-proteins in eukaryotes Figure taken from [134] with permission. In this review, we used the gene and protein
nomenclature for human and mice, which can be found at https://www.genenames.org/about/guidelines/ and http://www.informatics.jax.org/mgihome/nomen/gene.shtml,
respectively.
ing biological damage to others by generating 1 O2 and disrupting
the general metabolic processes of skin cells due to their degrada-
tion in over-exposed skin. Besides being photoactive, they are also
redox active and can become oxidized relatively easily. In fact, pho-
todegradation of vitamins in skin cells is likely to be responsible for
their metabolic failure and a major component of photoaging [118].
Note that the absorbance of many of these molecules extends to the
visible region of the spectrum, meaning that visible light also causes
effects similar to those known to occur with UVA (UVB is different
because of the direct reaction in DNA, as described above).
Other pigments that accumulate in the skin, such as melanin
and lipofuscin, are also known to generate 1 O2 . Baptista’s group
has shown that visible light generates similar mutagenic lesions to
those caused by UVA radiation [8,18]. That is why the skin, even
when protected by sunscreen, defends itself from the effects of
visible light, promoting pigmentation and leading to a tanned skin.
4. How visible light and UV radiation interact with opsins
4.1. Discovery of the opsins in the skin
Opsins are 7-transmembrane G-coupled receptors made up
of a protein moiety and the chromophore retinaldehyde, which
are present in organisms from archaea to metazoans [132]. It
has been established that the presently known mammalian pho-
topigments arose from three family lines: 1) rhodopsins and
cone opsins, pinopsin, VA-opsin, parapinopsin and encephalopsin
(ciliary opsins); 2) the RRH (retinal pigment epithelium-derived
rhodopsin homologue or peropsin) and RGR (retinal G-protein
coupled receptor) (photoisomerases); 3) the melanopsin line (rhab-
domeric opsins) (Fig. 6). The protein residue provides the optimal
microenvironment for the absorption of light at a particular
wavelength, and small differences near the chromophore allow
9
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
organisms to sense light of different wavelengths. Interestingly,
11-cis retinal can be isomerized to all-trans retinal by thermo-
activation, though this occurs only at a very low rate in the
mammalian retina [133].
In all opsins, photosensitivity results from the photoisomeriza-
tion of 11-cis retinal into all-trans retinal upon a photon capture.
Molecular transformations are then initiated, forming a partially
stable Meta II opsin, whose conformation enables it to activate the
G protein. Vertebrate opsins are known to activate G␣i/o or G␣q,
whereas the RRH and RGR do not interact with G proteins and can
bind to all-trans retinal [135,136].
For decades, opsins were associated with vision and irradiance
detection, while their discovery in non-ocular tissues was limited to
the non-mammalian pineal gland [137–139] and brain [140,141].
In 1998, the scientific community was struck by the news that
a novel opsin was found in the skin of the clawed frog Xenopus
laevis in melanin producing cells called melanophores, which was
why the new photopigment was given the name melanopsin [142].
Another surprise came from the realization that melanopsin was
more homologous to Octopus rhodopsin than to a typical verte-
brate opsin, even sharing the same signal transduction cascade
as the fruit fly, Drosophila, rhodopsin. But a real breakthrough of
the paradigm about mammalian photoreception was the discov-
ery by the same group [143] of melanopsin mRNA in the human
retinal ganglion cell layer. Axons of this subpopulation of ganglion
cells project into the suprachiasmatic nuclei, the central biological
clock, whose endogenous circadian oscillation is then adjusted by
the light/dark cycle information to exactly 24 h [144].
At the time, it was not known that opsins, including melanopsin,
could be expressed in the mammalian skin. But soon after, in
2001, Miyashita and colleagues [145] were the first to report the
expression of rhodopsin in the immortalized murine melanocytes
Melan-a, confirmed by Castrucci’s group [146], as well as in mouse
skin, followed by reports of opsin expression and photoreception
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
Table 4
Spectrum profile of mammalian opsins. Data was based on [15,150,172–175].
Range of detection (nm)
OPN1SW 370 – 500
OPN1MW 400 – 650
OPN1LW 400 – 680
OPN2 400 – 600
OPN3
OPN4 400 – 570
OPN5 370 – 450
by non-ocular tissues in non-mammalian vertebrates [147,148].
It took almost another decade before opsins were discovered in
human skin [149]. Although their functions remained elusive,
immunolabeling of rhodopsin-OPN2 and of S and L/M cone opsins-
OPN1 was demonstrated in the human epidermis [149]. Wicks and
colleagues [150] were able to confirm the expression of rhodopsin,
but none of the other opsins (encephalopsin-OPN3, melanopsin-
OPN4, neuropsin-OPN5) in human melanocytes, in contrast to the
findings in hairless mouse [151] and murine epidermal cells and
human skin [152], where the Opn5 gene and protein expression
were detected. In a subsequent article, however, Oncea’s group [43],
contradicting its previous report [150], demonstrated the presence
of OPN1SW, encephalopsin-OPN3 and neuropsin-OPN5 in human
melanocytes and keratinocytes. Confirming the conspicuousness
of rhodopsin transcripts in human skin, its expression was also
demonstrated in human keratinocytes [78] and hair follicles [74].
Castrucci’s group was the first to show the mRNA and pro-
tein levels of melanopsin Opn4 in murine Melan-a and B16-F10
cells [153], as well as confirmed the rhodopsin-Opn2, and in in
silico analysis of human skin cone opsins OPN1SW, OPN1MW,
and OPN1LW, rhodopsin-OPN2, encephalopsin-OPN3, melanopsin-
OPN4, and neuropsin-OPN5 [15] in exposed and unexposed skin.
In addition, Toh and colleagues [154] found the peropsin gene and
protein in human skin and keratinocytes. In 2019, in human dermal
fibroblasts, mRNA and protein levels of OPN1, OPN2, OPN3, OPN4,
and OPN5 were detected [155]. Immediately after, OPN4 expression
was also demonstrated in human keratinocytes and melanocytes
[156]. Importantly, RPE65, the isomerase essential for the regener-
ation of 11-cis retinal from all-trans retinal has also been found in
human keratinocytes [157].
The functionality of these opsins in the skin as photosensors of
visible and UV radiation will be discussed in the following sections.
4.2. Photophysical properties of opsins
As already mentioned, in terms of their structure, opsins belong
to a family of transmembrane proteins, containing seven ␣-helix
with a prosthetic photoactive group, which is called the retinal (an
aldehyde-form of vitamin A). Retinal, which exists in four different
forms, the more prevalent A1 (retinal) and A2 (3,4-dehydroretinal,
commonly found in vertebrates [158], and the less common A3 (3-
hydroxyretinal) and A4 (4-hydroxyretinal), is covalently bound to
a lysine residue at helix 7 and associated with G protein-coupled
receptors [158,159].
Opsins enable the transformation of photons into potential
energy that drives mechanical changes in the photoreceptor, which
are ultimately transduced to an intracellular G protein. Bacteri-
orhodopsin from Halobacterium halobium was the first isolated
and studied opsin. After light absorption (peak at 570 nm), bac-
teriorhodopsin is able to couple the cis-trans isomerization of the
retinal group with conformational changes in the protein, transfer-
ring protons from cytosol to the inter-membrane space and actively
transforming light into a proton gradient, which can be used for ATP
synthesis [160]. It is beyond the scope of this review to explore the
role of opsins in microbial, and thus, the reader is referred to excel-
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
Maximal absorption (nm) Reported to be sensitive to other wavelengths
360 (mice) 420 (humans)
510 (mice) 530 (humans)
560 nm (humans)
500 nm UVR (280–400 nm) and UVA radiation (365 nm)
No evidence in mammals
480 nm UVA radiation (365 nm)
380 nm
lent in-depth reviews [161,162]. As detailed below, the cis-retinal
undergoes substantial changes in its microenvironment during and
just after light absorption, as indicated by robust changes in its
absorption spectrum.
The detailed steps of these transformations are probably the
best-studied examples of the conversion of light to mechanical
energy. At every step, the process raises intriguing questions and
provides elegant solutions from nature. When the chromophore
absorbs a photon, it isomerizes from the 11-cis-retinal, which has
a bent shape, to the all-trans unbent form by the protonation
of a Schiff base, delocalizing ␲-electrons, and undergoing a red-
shift absorption from 500 nm to 540 nm (bathorhodopsin form)
[158,163]. These conformational changes trigger a rearrangement
in the protein structure, causing allosteric interactions involved in
the phototransduction responses.
Given the abundance and variability of the properties of opsins,
an abundance of questions surrounds the photophysics of opsins.
Why, for example, do most opsins function through the absorp-
tion of visible light, since retinal itself has an absorption maximum
in the UV region? Interestingly, the answer to this question not
only clarifies the red shift experienced by the chromophore itself,
but also explains why opsins are adapted to respond to such a
diverse range of wavelengths [158]. Inside rhodopsin, OPN2, the
apoprotein retinal binds to K296 in helix VII, forming a protonated
Schiff base, increasing electron delocalization within the retinal
electronic configuration and, consequently, shifting its absorption
spectrum towards visible light. A positive charge inside the protein
structure produces a large positive Gibbs energy potential, which is
reduced by the formation of an ion pair with a negatively charged
amino acid residue. Fine tuning of the distances and strengths of
these interactions allow shifts in the absorption spectra in the hun-
dreds of nanometers, explaining why opsins work in such a wide
range of wavelengths [164]. As a consequence, the retinal itself has
a maximal absorption in the UVR (380 nm), but this absorption is
shifted to other wavelengths, as shown in Table 4.
After light absorption, the major photochemical event is a pho-
toisomerization reaction from the 11-cis retinal to the all-trans
form. Several intermediates have been identified during rhodopsin
photocycle within timescales varying from picoseconds to mil-
liseconds [163–165]. The large quantum yield (0.65) [166] and
the velocity of the photoisomerization (the primary ground-state
rhodopsin photoproduct occurs within 200 fs [167]), has been
intriguing the scientific community for quite some time. The
detailed mechanism for this one-way, extremely fast and efficient
photoisomerization reaction was initially proposed theoretically
and recently proven experimentally to be the consequence of the
crossing between the potential energy surfaces of ground and
excited electronic states, in a so-called conical intersection [168].
The regeneration of 11-cis retinal is processed with the help of the
RPE 65, well known to catalyze this conversion in the retinal pig-
ment epithelium in the mammalian eye [169]. Unlike the majority
of the mammalian opsins, melanopsin OPN4 is a bistable photopig-
ment [170], meaning that it may exist as a mixture of two steady
states: the 11-cis resting form and the all-trans excited form. This
photopigment may exhibit the ability to regenerate the 11-cis reti-
10
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
nal without the need of an isomerase, similar to what happens in
invertebrates, where longer light wavelengths can turn all-trans
back into 11-cis retinal [171].
Even though the thermal induced cis-trans isomerization has
a very high energy barrier in the visual pigments, some opsins
can also respond to temperature changes, with light-independent
roles such as temperature discrimination [176]. This is intrigu-
ing, considering that the structure of classical opsins is designed
to avoid electrical dark-noise signals [177]. However, there are
conditions that can lead to a decrease in the thermal activation
barrier. For example, the deprotonation of the 11-cis Schiff base
decreases the energy barrier of the cis-trans isomerization from ∼45
to 27 kcal/mol. Therefore, if the pH of the opsin vicinity is slightly
elevated, opsin deprotonation can occur, decreasing the energy bar-
rier for thermal activation, whereupon the receptor may start to
respond to subtle temperature variations [178]. Recent evidence
points to the opsin thermal activation being highly dependent on
the entropy-driven breakup of the hydrogen bonding networks
(HBNs) that usually hinder the thermal isomerization reaction.
Indeed, rhodopsin mutants that have disrupted HBNs in the vicinity
of the 11-cis retinyl have significantly decreased thermal activa-
tion energy [179]. This explains earlier observation that the thermal
sensor in Drosophila larvae depends on the expression of different
rhodopsins [180]. The thermosensing ability of opsins in mammals
has been explored in recent studies, though it remains elusive.
The first report of mammalian opsins sensing thermal energy was
reported in pioneering work by Eisenbach’s group [181]. In these
seminal reports, sperm cell thermotaxis was shown to be defective
in Opn2 or Opn4 knockout mice and dependent on phospholipase
C (PLC) and cyclic nucleotides signaling pathways [181,182]. In
skin cells, Castrucci’s group was also pioneer in demonstrating that
OPN4 acts as a thermosensor in normal and malignant melanocytes,
which feeds the local circadian clock with environmental temper-
ature [183].
Collectively, as described above, there are solid photochemical-
related mechanisms that provide the foundation for the thermo-
activation of opsins, which is followed by functionally driven
reports that have validated such concepts in in vitro and in vivo
experiments. Therefore, opsins have been confirmed to sense heat
as well as light.
4.3. Advancement in the field: a historical view of opsin functions
in the skin
4.3.1. UVR sensor
In 2010, Castrucci’s group reported the first mechanism of OPN2
signaling in a murine melanoma cell line, B16-F10. The authors
demonstrated that Opn2 transcripts were increased by endothelin,
and that PLC, calcium, calcium/calmodulin kinase II, and protein
kinase C were involved in the process [146].
In 2011, Wicks and colleagues demonstrated that UVR (2 kJ/m2 ,
[150]) evoked a retinal-dependent calcium transient in human
melanocytes. Calcium rise was shown to be mainly dependent on
UVA wavelength and intracellular calcium storages, G-protein sig-
naling and PLC. Only OPN2 transcript was detected in this study,
and UVA-induced calcium increase was markedly reduced when it
was silenced. Moreover, a higher UVR dose (40 kJ/m2 ) led to a tem-
poral increase of melanin levels, which was associated with UVA
and retinal requirements. This was the first study to suggest that
immediate pigment darkening (IPD) might be the result of de novo
melanin synthesis [150], opposing a canonical view of IPD which
had hitherto been associated with the oxidation of pre-existing
melanin [58]. In a subsequent study, the same group [175] elegantly
demonstrated that UVR elicits a retinal-dependent increase in ionic
current in human melanocytes, which was mainly dependent on
UVA but not UVB wavelength. The UVR-dependent photocurrent
11
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
was dependent on the transient receptor potential ankyrin 1 chan-
nel (TRPA1), PLC, and calcium. Furthermore, UVR-induced early
melanin synthesis was also dependent on TRPA1 [175]. Interest-
ingly, UVR was shown to transiently depolarize the membrane of
human melanocytes, which delayed TRPA1 inactivation, leading to
sustained calcium levels [184].
Concomitantly, UVA (10–100 kJ/m2 ) and violet light
(100–500 kJ/m2) exposure was shown to increase OPN2 tran-
scripts and downregulate differentiation markers in human
keratinocytes. Over- or down-expressing OPN2 mRNA, resulted in,
respectively, a decrease or increase in differentiation markers [89].
In 2014, Oancea’s group demonstrated that UVR activates a protein
G␣q/11 dependent pathway that leads to PLC activation and
hydrolysis of phosphatidylinositol (4,5)-bisphosphate (PIP2 ) into
diacylglycerol (DAG) and inositol 1, 4, 5-trisphosphate (IP3 ). PIP2
regulates TRPA1- dependent photocurrents (extracellular calcium
influx) while IP3 stimulates calcium release from intracellular
stores. The combination of TRPA1-mediated calcium entry and
calcium release from internal storage leads to sustained calcium
levels, which resulted in melanin synthesis [184].
Interestingly, mouse and human OPN5 have been demonstrated
to be sensitive to UVR irradiation (380 nm [152]), and human
OPN5 expressed in HEK 293 cells responded to light (470−490 nm,
2.5 × 10−8 kJ/m2 ) with transient calcium rise and to UVR radiation
(352–380 nm, 3.7 × 10-4 – 1.1 10-3 kJ/m2 ) with calcium rise, cAMP
production, and MAP kinase activation [185].
In 2017, Castrucci’s group explored the effect of UVA radiation
in association with heat shock on murine melanocytes. UVA radi-
ation (4.4 kJ/m2 ) was shown to increase Opn4, Clock, and Bmal1
transcripts in malignant melanocytes compared to unexposed cells.
Moreover, UVA radiation led to a transient increase in melanin lev-
els, as a result of IPD processes. It should be emphasized that all
UVA-related data explained above was carried out at constant tem-
perature (37 ◦ C). Surprisingly, the authors found that when UVA
radiation was associated with temperature increase (up to 40 ◦ C) all
UVA-induced responses were abolished, demonstrating that tem-
perature could antagonize UVA-dependent effects [186]. This is
an important factor which has been neglected in most reports,
since the majority of the literature ignores the temperature com-
ponent in photobiology experimental designs. These data highlight
the importance of controlling temperature during UV/visible light
experiments since opsins can also act as a temperature sensor.
The process of melanogenesis within skin melanocytes and
the transfer of melanin granules to the adjacent keratinocytes are
important defensive mechanisms against UV radiation. Hu and col-
leagues [187] reported that UVA (30 kJ/m2 ) and UVB (200 kJ/m2 )
elicited intracellular calcium rise in human melanocytes only in
the presence of retinal, which led to melanosome transfer in a
co-culture of melanocytes and keratinocytes. This process was
enhanced when the cell culture was subject to simultaneous UVA
and UVB irradiation, and calcium influx was abolished when TRPM1
channel was silenced. Nevertheless, despite similar efficiency of
UVA and UVB in activating melanosome transfer, UVA is less effec-
tive to stimulate melanin synthesis compared to UVB radiation.
Although UVB radiation leads to more significant DNA damage, it
also activates protective mechanisms such as melanin production
[187].
Castrucci’s group, using pharmacological and gene silencing
strategies, demonstrated that OPN4 is essential for UVA-induced
IPD in murine melanocytes. Moreover, UVA signaled through a
pathway dependent on calcium, calcium/calmodulin kinase II,
nitric oxide (NOS), and cyclic guanosine monophosphate (cGMP).
Interestingly, silencing Opn2 also abolished IPD, thus showing a
possible compensatory mechanism between OPN2 and OPN4 in
both normal and malignant melanocytes [15,153]. It should be
highlighted that in this experimental model, UVA induced a tran-
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
sient rise in melanin levels, and not a sustained increase as observed
by Oncea’s group [150,174,175,184]. The reason for such difference
may lie in different characteristics of the UV lamps, contami-
nation with UVB, difference in irradiance, and cellular model as
extensively discussed elsewhere [15,153,186]. A year later, blue
light radiation (20 kJ/m2 ) was reported to reduce DNA synthesis
and stimulate differentiation in primary human epidermal ker-
atinocytes. Upon OPN3 gene silencing, a slight decrease in the
differentiation markers was found, which suggests that OPN3 may
be required for barrier function in vivo. The role of OPN1SW was not
evaluated in this study, but its role as a putative blue light receptor
in this model was not discarded [188]. UVA radiation (100 kJ/m2 )
increased the protein levels of OPN1, OPN3, and OPN5 without
leading to DNA damage in human fibroblasts. Upon knockdown of
OPN3, the UVA-induced increase of calcium level, the phosphory-
lation of CREB and the activation of calmodulin-dependent protein
kinase were abolished, along with the matrix metalloproteinases.
Thus, OPN3 was suggested to be the major player in UVA-elicited
photoaging [189] although no screening of the other opsins was
performed. Most studies in the literature show the involvement
of OPN3 as a light/UVA sensor using gene silencing and pharma-
cological strategies. However, a recent study by Oancea’s group
has provided insights into a light-independent role of OPN3. In an
elegant paper, OPN3 was ruled out as the melanocyte blue light
receptor using spectroscopy analysis, i.e., OPN3 did not absorb in
any UV/visible wavelength, despite its ability to bind to retinal [44].
It should be noted that the first attempt to characterize mouse and
human OPN3 was performed in 2016, but it was not successful
[172]. These findings demonstrated the inability of OPN3 to absorb
photons, thus ruling it out as a light sensor, despite its ability to bind
to retinal. Along the same lines, OPN3 was shown to be a negative
regulator of melanogenesis in human melanocytes, independently
of UV and visible light, by inhibiting a MC1R (melanocortin type
1 receptor)-dependent cAMP pathway [44]. A more recent report
has also brought more evidence of a light and thermo-independent
role of OPN3. In human melanocytes, OPN3 gene knockdown led
to apoptosis in a calcium-dependent manner, with increased mito-
chondria permeability and caspase activation [190].
In 2020, Castrucci’s group demonstrated a novel and interest-
ing role of OPN4. With three daily low doses of UVA radiation
(4.4 kJ/m2 ), a reduction on cellular proliferation was found in
normal and malignant melanocytes; however, cell death, in an
apoptosis-dependent manner, was only found in the latter group.
Daily doses of UVA also led to persistent pigment darkening (PPD)
in both cell types. Interestingly, upon Opn4 gene knockout by Clus-
tered Regularly Interspaced Short Palindromic Repeats (CRISPR)
technique, all UVA-induced effects were lost. In this study, an
increased molecular clock activation was found in Opn4 KO cells
compared to wild type counterparts, which suggests a putative
compensatory mechanism by other opsins, such as OPN2, which
could lead to increased responsiveness. Moreover, bioinformat-
ics analysis revealed that OPN4 expression gradually decreases
with human melanoma progression [191]. Therefore, this study
provided initial evidence of OPN4 functions in PPD and in UVA-
induced apoptosis, as well as a putative role in the carcinogenic
process of cutaneous melanoma [191]. More recently, Oancea’s
group demonstrated that UVA-induced ROS generation leads to
melanin synthesis through two different temporally distinct mech-
anisms. The early process is upstream the UVA-induced signaling
cascade activation. The second one requires retinal and G␣q/11-
dependent calcium mobilization into the mitochondria. Therefore,
this study demonstrated a novel evidence that mitochondria of
melanocytes are able to respond to UVA radiation effects, contribut-
ing to melanin synthesis; however, the identity of the opsin that
participates in UVA phototransduction cascade, in this particular
model, remains elusive [192].
12
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
4.3.2. Visible light sensor
Murine cell experiments by Castrucci’s group have also led to
advances in the knowledge of the physiological mechanisms reg-
ulated by the skin photosensitive system. When these cells were
kept in constant dark, twenty-four hours after visible light stimu-
lation (white light 0.85 kJ/m2 at constant temperature) a reduction
of Opn2 expression was seen in malignant melanocytes (B16-F10).
Meanwhile, 36 and 42 h after the same stimulus, an increase of
Opn4 mRNA was also observed in malignant cells, compared to
controls kept in constant dark. No effects were detected in nor-
mal melanocytes (Melan-a). OPN2 and OPN4 protein was detected
by immunocytochemistry and imaging flow cytometry in both cell
lines, and upon light stimulation OPN4 migrated from the per-
inuclear region to the membrane only in malignant melanocytes
[153]. Twenty-four hours after visible light stimulation, Per1, Per2,
and Clock expression was increased compared to unexposed malig-
nant melanocytes, while no effect was found on the clock genes
of normal melanocytes. In response to visible light, melanin lev-
els were unaffected in both cellular types [153]. Collectively, the
above-mentioned data in the murine model demonstrated that a
functional opsin system was expressed in melanocytes, and under
these experimental conditions, seemed to be more sensitive in
malignant than in normal melanocytes [153].
In human keratinocytes, violet light (380 nm, 12 kJ/m2 ) induced
the highest level of intracellular calcium, which was inhibited when
retinal was withdrawn from the medium or a broad protein G
inhibitor (suramin) was added. In addition, upon peropsin gene
silencing, the violet light-induced calcium flux was lost [154].
In an interesting study using human hair follicles, blue light
(453 nm, 32 kJ/cm2 ) was shown to prolong the anagen phase in
an ex vivo model, which was associated with sustained prolif-
eration, while red light, at the same dose, did not affect hair
growth. OPN3 gene silencing in the hair follicles decreased the
majority of proliferation- and apoptosis-related genes as well as
abolishing the blue light-induced effects [74]. In melanocytes from
phototype IV human individuals, blue light (415 nm, 500 kJ/m2 )
increased OPN3- dependent pigmentation [14]. Unlike a previous
report [43], Passeron’s group found no opsins but OPN3 in human
melanocytes and that blue light stimulation did not affect its tran-
script levels. However, blue light triggered a signaling pathway
which involved increased calcium levels, activation of calmodulin-
dependent protein kinase II, phosphorylation of CREB, extracellular
signal-regulated kinase, p38, upregulation of microphthalmia-
associated transcription factor (MITF), and increased expression
of the melanogenic enzymes, tyrosinase, and dopachrome tau-
tomerase. Upon OPN3 silencing, blue light-induced signaling
cascade, described above, was suppressed, and consequently no
melanin increase was seen. Interestingly, this study also ruled out
the oxidative stress as a participant in this process, thus strength-
ening the evidence of an opsin-based detection system [14].
Also in 2019, Buhr and colleagues demonstrated OPN5 expres-
sion in mouse vibrissal pad and ear pinna skin. Under light/dark
cycle, the skin failed to be synchronized to the light-dark cycle
in the absence of retinal as well as in the Opn5−/− mice. Another
evidence of OPN5-neuropsin function arose from ex vivo skin exper-
iments kept in complete darkness and exposed to 27 kJ/m2 of violet
light (at 36 ◦ C). Such light stimulus entrained the molecular clock
entrainment, which was abolished in the skin from Opn5−/− mice.
Interestingly, the skin molecular clock of blind mice, with rod and
cone degeneration associated with OPN4-melanopsin deletion, was
synchronized to the light/ dark cycle which together with the pre-
vious data demonstrate that the skin can directly sense light, and
this is dependent on OPN5, and not OPN4 [193].
Fan and colleagues elegantly showed that daily blue light
(463 ± 50 nm, 20 kJ/m2 ) for 10 days stimulated hair follicle anagen,
leading to a significant hair growth compared to unexposed ani-
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
mals. Green light stimulation (522 ± 50 nm), at the same dose, also
stimulated hair growth but less effectively. Blue light-induced hair
growth was lost when the optic nerve was crushed and reduced in
animals with rod and cone degeneration. Interestingly, in Opn4−/−
mice, blue light stimulation did not affect hair growth compared
to wild type animals. Mechanistically, blue light stimulation to the
eyes increased systemic sympathetic activity and norepinephrine
levels in the skin, and activated hedgehog pathways in wild type
animals. All these effects were lost in Opn4−/− animals [194].
In 2020, Kusumoto and colleagues reported OPN4 expression
in human skin tissue and in primary melanocytes, keratinocytes,
and fibroblasts. A new variant of Opn4 was detected, but it was
considered non-functional due to the lack of retinal binding site. In
human fibroblasts kept in dark, blue light stimulation (450–488 nm,
10–30 ␮mol m−2 s−1 during 0–20 min), applied in cells kept at
37 ◦ C, led to calcium influx and ERK1/2 phosphorylation, which
were reduced when OPN4 was antagonized with opsinamide [156].
The inability of OPN3 to absorb UV/visible light photons
reported by Ozdeslik and colleagues [44] calls for a deeper investi-
gation into the literature as several studies, described above, have
demonstrated that the light-induced effects were lost when the
opsin expression was reduced. However, the loss or reduction of
biological effects upon reducing OPN3 levels does not guarantee its
function as a light sensor. One may suggest that OPN3 may partic-
ipate as a player in the signaling cascade but not as a sensor. Or
considering that over the past decades, opsins have been shown to
be intriguing molecules: they were historically seen as light sensors
but were shown to act as thermosensor, and, more recently, opsins
were reported to be involved in taste discrimination in Drosophila
[195]. Therefore, it would not be surprising for opsins to also per-
form unexpected roles as GPCRs. Another important feature of
OPN3 is its wide distribution in several “blind” tissues, which do not
receive light, thus arguing for light-independent effects, despite its
canonical ability to bind to retinal.
The caveats of pharmacological and gene silencing techniques
must be considered. Caution must therefore be used when inter-
preting experiments and calling an opsin a light sensor. Such
confusion has been seen in the rapid effects of aldosterone. In
recent years, several experiments showed that G-protein coupled
estrogen receptor 1 (GPER1) was necessary for inducing the rapid
effects of aldosterone. Those experiments were mainly based on
gene silencing and pharmacological strategy, similarly to OPN3-
related experiments. In fact, the absence of GPER1 led to abolish-
ment of many aldosterone-induced effects, and as consequence,
GPER1 received attention as a new receptor for aldosterone. How-
ever, further investigation has demonstrated that aldosterone does
not bind GPER1 in the membrane (review in [196]). As is the case
of aldosterone and its inability to bind to GPER1, may be analo-
gous to the inability of OPN3 to be activated by light according
to spectroscopy data [44]. Indeed, OPN3 may participate in the
blue light-induced pathway, as it has been clearly shown in several
studies; however, its role as the effective sensor remains unclear.
Taken together, since the first report in 2001, and especially
after 2011, the knowledge of the photosensitive system of the
skin has seen a significant advancement as many opsin-dependent
skin physiological processes and putative targets were discovered
(Fig. 1), (Graphical Abstract). Still, there are many unknowns and
open questions. With gene editing and omics approaches, new dis-
coveries will be made and putative drug targets for skin-related dis-
eases will be revealed and translated into clinical care treatments.
5. Concluding remarks
Understanding how UV radiation and light photons interact
with the skin has been an ongoing challenge but a rewarding adven-
ture. The beauty that lies within the skin tissue must be appreciated,
13
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
with its different cell types, the complex communication between
its cells, the signaling pathways and biological processes that take
place in this organ. A significant advancement in the photobiol-
ogy of the skin has been achieved by the hard work of several
groups worldwide. To further unravel more layers of knowledge
in this system, we understand that a more integrative approach is
needed. In other words, the mechanism of photons’ interaction with
chromophores and opsins must be addressed in future research
projects. Nonetheless, the contribution of previous studies focus-
ing the theme cannot be disregarded. On the contrary, it must be
acknowledged!
Due to space limitation, we could not properly give credit to
several important studies that laid the foundation of our current
knowledge. The understanding of how light is detected by skin
cells might be dependent on mutual interaction between opsins
and chromophores, which itself is a challenge to be experimen-
tally addressed. Within this line, our goal was to provide a critical
thinking to the reader that UV and light photons can interact simul-
taneously with both skin opsins and chromophores, as well as the
benefits and the harm resulting from the exposure. We hope the
reader may see the skin as a complex light-detecting organ with
several phenomena taking place driven by photon stimulation. A
better comprehension of such processes will increase our knowl-
edge of skin biology as well as improve the therapy of skin-related
diseases. The future is promising.
Declaration of Competing Interest
All authors state no conflict of interest that could have impacted
the development of this study.
Acknowledgements
This work was supported by the Sao Paulo Research Founda-
tion (FAPESP, grants 2017/24615-5 and 2018/14728-0 to Castrucci
AML; CEPID REDOXOMA 2013/07937-8 to Baptista MS) and by
the National Council of Technological and Scientific Development
(CNPq grants 303078/2019-7 to Castrucci AML; 303831/2019-7
to Baptista MS). Moraes MN is a Young Investigator of FAPESP
(2017/26651-9). de Assis LVM was a fellow of FAPESP (2018/16511-
8). Funding sources had no involvement in the study design, in the
collection, analysis and interpretation of data, in the writing of the
report, and in the decision to submit the article for publication.
References
[1] U. Leiter, T. Eigentler, C. Garbe, Epidemiology of skin cancer, Adv. Exp. Med.
Biol. 810 (2014) 120–140, http://dx.doi.org/10.1007/978-1-4939-0437-2 7.
[2] L. Cohen, M.A. Brodsky, R. Zubair, I. Kohli, I.H. Hamzavi, M. Sadeghpour,
Cutaneous interaction with visible light: what do we know, J. Am. Acad.
Dermatol. (2020), http://dx.doi.org/10.1016/j.jaad.2020.03.115.
[3] AAD (American Academy of Dermatology), Vitamin D and UV exposure,
(n.d.). https://www.aad.org/media/stats/prevention-and-care/vitamin-d-
and-uv-exposure.
[4] Z. Apalla, A. Lallas, E. Sotiriou, E. Lazaridou, D. Ioannides, Epidemiological
trends in skin cancer, Dermatol. Pract. Concept. 7 (2017) 1–6, http://dx.doi.
org/10.5826/dpc.0702a01.
[5] TMR (Transparency Market Research), Sun Care Market (Type - SPF 6-14,
SPF 15-30, SPF 30-50, SPF 50+; Form - Creams, Gel, Lotion, Powder, Liquid,
Wipes, Spray, Colored) - Global Industry Analysis, Size, Share, Growth,
Trends and Forecast 2016-2024, 2015.
[6] L. Kolbe, How much sun protection is needed?: Are we on the way to
full-spectrum protection? J. Invest. Dermatol. 132 (7) (2012) 1756–1757,
http://dx.doi.org/10.1038/jid.2012.148.
[7] F. Liebel, S. Kaur, E. Ruvolo, N. Kollias, M.D. Southall, Irradiation of skin with
visible light induces reactive oxygen species and matrix-degrading
enzymes, J. Invest. Dermatol. 132 (7) (2012) 1901–1907, http://dx.doi.org/
10.1038/jid.2011.476.
[8] P.N. Tonolli, O. Chiarelli-Neto, C. Santacruz-Perez, H.C. Junqueira, I.S.
Watanabe, F.G. Ravagnani, W.K. Martins, M.S. Baptista, Lipofuscin generated
by UVA turns keratinocytes photosensitive to visible light, J. Invest.
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
Dermatol. 137 (11) (2017) 2447–2450, http://dx.doi.org/10.1016/j.jid.2017.
06.018.
[9] E. Markiewicz, O.C. Idowu, Melanogenic difference consideration in ethic
skin type: a balance approach between skin brightening applications and
beneficial sun exposure, Clin. Cosm. Investig. Dermatol. 13 (2020) 215–232,
http://dx.doi.org/10.2147/CCID.S245043.
[10] M. Brenner, V.J. Hearing, The protective role of melanin against UV damage
in human skin, Photochem. Photobiol. 84 (3) (2008) 539–549, http://dx.doi.
org/10.1111/j.1751- 1097.2007.00226.x.
[11] L. Zastrow, N. Groth, F. Klein, D. Kockott, J. Lademann, R. Renneberg, L.
Ferrero, The missing link - Light-induced (280-1,600 nm) free radical
formation in human skin, Skin Pharmacol. Physiol. 22 (1) (2009) 31–44,
http://dx.doi.org/10.1159/000188083, 2009.
[12] S. Cho, M.H. Shin, Y.K. Kim, J.E. Seo, Y.M. Lee, C.H. Park, J.H. Chung, Effects of
infrared radiation and heat on human skin aging in vivo, J. Investig.
Dermatol. Symp. Proc. 14 (1) (2009) 15–19, http://dx.doi.org/10.1038/
jidsymp.2009.7.
[13] S. George, M.R. Hamblin, H. Abrahamse, Effect of red light and near infrared
laser on the generation of reactive oxygen species in primary dermal
fibroblasts, J. Photochem. Photobiol. B, Biol. 188 (2018) 60–68, http://dx.doi.
org/10.1016/j.jphotobiol.2018.09.004.
[14] C. Regazzetti, L. Sormani, D. Debayle, F. Bernerd, M.K. Tulic, G.M. De Donatis,
B. Chignon-Sicard, S. Rocchi, T. Passeron, Melanocytes sense blue light and
regulate pigmentation through opsin-3, J. Invest. Dermatol. 138 (1) (2017)
171–178, http://dx.doi.org/10.1016/j.jid.2017.07.833.
[15] L.V.M. de Assis, M.N. Moraes, K.K. Magalhaes-Marques, A.M.L. Castrucci,
Melanopsin and rhodopsin mediate UVA-induced immediate pigment
darkening:unravelling the photosensitive system of the skin, Eur. J. Cell Biol.
97 (3) (2018) 150–162, http://dx.doi.org/10.1016/j.ejcb.2018.01.004.
[16] K.H. Kaidbey, P.P. Agin, R.M. Sayre, A.M. Kligman, Photoprotection by
melanin—a comparison of black and Caucasian skin, J. Am. Acad. Dermatol. 1
(3) (1979) 249–260, http://dx.doi.org/10.1016/S0190-9622(79)70018-1.
[17] O. Chiarelli-Neto, C. Pavani, A.S. Ferreira, A.F. Uchoa, D. Severino, Generation
and suppression of singlet oxygen in hair by photosensitization of melanin,
Free Rad. Biol. Med. 51 (6) (2011) 1195–1202, http://dx.doi.org/10.1016/j.
freeradbiomed.2011.06.013.
[18] O. Chiarelli-Neto, A.S. Ferreira, W.K. Martins, C. Pavani, D. Severino, F. Faião-
Flores, S.S. Maria-Engler, E. Aliprandini, G.R. Martinez, P. Di Mascio, M.G.
Medeiros, M.S. Baptista, Photosensitization of melanin and the effect of
visible light on skin and hair, PLoS One 9 (11) (2014) e113266, http://dx.doi.
org/10.1371/journal.pone.0113266.
[19] O. Chiarelli-Neto, M.S. Baptista, Photosensitizing properties of melanin upon
excitation with visible light, Trends Photochem. Photobiol. 17 (2016) 57–68.
[20] N.A. Vashi, M.B.D.C. Maymone, R.V. Kundu, Aging differences in ethnic skin,
J. Clin. Aesthet. Dermatol. 9 (1) (2016) 31–38.
[21] S.V. Davis, Vitamin D deficiency and type 2 diabetes in African Americans:
the common denominators, Diabetes Spectr. 24 (3) (2011) 148–153, http://
dx.doi.org/10.2337/diaspect.24.3.148.
[22] IARC 1992 IARC Monograph on the evaluation of carcinogenic risks to
human. Solar and ultraviolet radiation, IARC Monogr. Eval. Carcinog. Risks
Hum. 55 (1992) 1–316, PMID 1345607.
[23] M.S. Matsui, A. Hsia, J.D. Miller, K. Hanneman, H. Scull, K.D. Cooper, E. Baron,
Non- sunscreen photoprotection: antioxidants add value to a sunscreen, JID
Symp. Proc. 14 (1) (2009) 56–59, http://dx.doi.org/10.1038/jidsymp.2009.14.
[24] B. Eberlein-König, J. Ring, Relevance of vitamins C and E in cutaneous
photoprotection, J. Cosmet. Dermatol. 4 (1) (2005) 4–9, http://dx.doi.org/10.
1111/j.1473-2165.2005.00151.x.
[25] J.V. Freitas, H.C. Junqueira, W.K. Martins, M.S. Baptista, L.R. Gaspar,
Antioxidant role on the protection of melanocytes against visible
light-induced photodamage, Free Rad. Biol. Med. 131 (2019) 399–407,
http://dx.doi.org/10.1016/j.freeradbiomed.2018.12.028.
[26] IARC, IARC handbooks of cancer prevention Sunscreens, Volume 5, 2001.
[27] L.K. Dennis, L.E.B. Freeman, M.J. VanBeek, Sunscreen use and the risk for
melanoma: a quantitative review, Ann. Intern. Med. 139 (12) (2003)
966–978, http://dx.doi.org/10.7326/0003-4819-139-12-200312160-00006.
[28] R.P. Gallagher, Sunscreens in melanoma and skin cancer prevention, CMAJ
173 (3) (2005) 244–245, http://dx.doi.org/10.1503/cmaj.050762.
[29] J.C. DiNardo, C.A. Downs, Dermatological and environmental toxicological
impact of the sunscreen ingredient oxybenzone/benzophenone-3, J. Cosmet.
Dermatol. 17 (1) (2018) 15–19, http://dx.doi.org/10.1111/jocd.12449.
[30] FDA proposes changes to US sunscreen rules, in: C&EN Glob. Enterp., 2019,
http://dx.doi.org/10.1021/cen-09709-polcon1.
[31] C.A. Downs, E. Kramarsky-Winter, R. Segal, J. Fauth, S. Knutson, O. Bronstein,
F.R. Ciner, R. Jeger, Y. Lichtenfeld, C.M. Woodley, P. Pennington, K. Cadenas,
A. Kushmaro, Y. Loya, Toxicopathological effects of the sunscreen UV filter,
oxybenzone (benzophenone-3), on coral planulae and cultured primary
cells and its environmental contamination in Hawaii and the U.S. Virgin
Islands, Arch. Environ. Contam. Toxicol. 70 (2016) 265–288, http://dx.doi.
org/10.1007/s00244-015-0227-7.
[32] R. Danovaro, L. Bongiorni, C. Corinaldesi, D. Giovannelli, E. Damiani, P.
Astolfi, L. Greci, A. Pusceddu, Sunscreens cause coral bleaching by promoting
viral infections, Environ. Health Perspect. 116 (4) (2008) 421–572, http://dx.
doi.org/10.1289/ehp.10966.
[33] State of Hawaii, 2018, S.B. 2571. Available on: https://www.capitol.hawaii.
gov/session2018/bills/SB2571 CD1 .pdf.
14
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
[34] Z. Naeem, Vitamin d deficiency- an ignored epidemic, Int. J. Health Sci.
(Qassim) 4 (1) (2010) V–VI.
[35] S. Pilz, N. Verheyen, M.R. Grübler, A. Tomaschitz, W. März, Vitamin D and
cardiovascular disease prevention, Nat. Rev. Cardiol. 13 (2016) 404–417,
http://dx.doi.org/10.1038/nrcardio.2016.73.
[36] R. Civitelli, K. Ziambaras, Calcium and phosphate homeostasis: concerted
interplay of new regulators, J. Endocrinol. Invest. 34 (7) (2011) 3–7.
[37] C. Aranow, Vitamin D and the immune system, J. Investig. Med. 59 (2012)
881–886, doi:10.231/JIM.0b013e31821b8755.
[38] S. Penckofer, J. Kouba, M. Byrn, C.E. Ferrans, Vitamin D and depression:
where is all the sunshine, Issues Ment. Health Nurs. 31 (2010) 385–393,
http://dx.doi.org/10.3109/01612840903437657.
[39] A.J. Samanek, E.J. Croager, P. Gies, E. Milne, R. Prince, A.J. McMichael, R.M.
Lucas, T. Slevin, Estimates of beneficial and harmful sun exposure times
during the year for major Australian population centres, Med. J. Aust. 184
(7) (2006) 338–341.
[40] M.F. Holick, T.C. Chen, Vitamin D deficiency: a worldwide problem with
health consequences, Am. J. Clin. Nutr. 87 (4) (2008) 1080S–1086S, http://
dx.doi.org/10.1093/ajcn/87.4.1080S.
[41] W.B. Grant, C.F. Garland, E.D. Gorham, An estimate of cancer mortality rate
reductions in Europe and the US with 1,000 IU of oral vitamin D per day,
Recent Results Cancer Res. 174 (2007) 225–234, http://dx.doi.org/10.1007/
978-3-540-37696-5 20.
[42] CDC, Skin Cancer Cases and Costs on the Rise from 2002-2011, US
Department Health and Human Diseases, 2014 https://www.cdc.gov/media/
releases/2014/p1110-skin-cancer.html.
[43] K. Haltaufderhyde, R.N. Ozdeslik, N.L. Wicks, J.A. Najera, E. Oancea, Opsin
expression in human epidermal skin, Photochem. Photobiol. 91 (1) (2015)
117–123, http://dx.doi.org/10.1111/php.12354.
[44] R.N. Ozdeslik, L.E. Olinski, M.M. Trieu, D.D. Oprian, E. Oancea, Human
nonvisual opsin 3 regulates pigmentation of epidermal melanocytes
through functional interaction with melanocortin 1 receptor, Proc. Natl.
Acad. Sci. U. S. A. 116 (23) (2019) 11508–11517, http://dx.doi.org/10.1073/
pnas.1902825116.
[45] N.Y. Leung, C. Montell, Unconventional roles of opsins, Annu. Rev. Cell Dev.
Biol. 33 (2017) 241–264, http://dx.doi.org/10.1146/annurev-cellbio-
100616-060432.
[46] J.F. Duffy, C.A. Czeisler, Effect of light on human circadian physiology, Sleep
Med. Clin. 4 (2) (2009) 165–177, http://dx.doi.org/10.1016/j.jsmc.2009.01.
004.
[47] T. Roenneberg, T. Kantermann, M. Juda, C. Vetter, K.V. Allebrandt, Light and
the human circadian clock, Handb. Exp. Pharmacol. 217 (2013) 311–331,
http://dx.doi.org/10.1007/978-3-642-25950-0-13.
[48] T. Roenneberg, C.J. Kumar, M. Merrow, The circadian clock and human
health, Curr. Biol. 26 (10) (2016) R432–443, http://dx.doi.org/10.1016/j.cub.
2016.04.011.
[49] N. Fleury, S. Geldenhuys, S. Gorman, Sun exposure and its effects on human
health: mechanisms through which sun exposure could reduce the risk of
developing obesity and cardiometabolic dysfunction, Int. J. Environ. Res.
Public Health 13 (10) (2016) 999, http://dx.doi.org/10.3390/ijerph13100999.
[50] D. Liu, B.O. Fernandez, A. Hamilton, N.N. Lang, J.M.C. Gallagher, D.E. Newby,
M. Feelisch, R.B. Weller, UVA irradiation of human skin vasodilates arterial
vasculature and lowers blood pressure independently of nitric oxide
synthase, J. Invest. Dermatol. 134 (7) (2014) 1839–1846, http://dx.doi.org/
10.1038/jid.2014.27.
[51] G.M. Halliday, S.N. Byrne, An unexpected role: UVA-induced release of nitric
oxide from skin may have unexpected health benefits, J. Invest. Dermatol.
134 (7) (2014) 1791–1794, http://dx.doi.org/10.1038/jid.2014.33.
[52] R.B. Weller, Sunlight has cardiovascular benefits independently of vitamin D,
Blood Purif. 41 (1-3) (2016) 130–134, http://dx.doi.org/10.1159/000441266.
[53] K. Ondrusova, M. Fatehi, A. Barr, Z. Czarnecka, W. Long, K. Suzuki, S.
Campbell, K. Philippaert, M. Hubert, E. Tredget, P. Kwan, N. Touret, M.
Wabitsch, K.Y. Lee, P.E. Light, Subcutaneous white adipocytes express a light
sensitive signaling pathway mediated via a melanopsin/TRPC channel axis,
Sci. Rep. 7 (1) (2017) 16332, http://dx.doi.org/10.1038/s41598-017-16689-4.
[54] P.G. Lindqvist, E. Epstein, K. Nielsen, M. Landin-Olsson, C. Ingvar, H. Olsson,
Avoidance of sun exposure as a risk factor for major causes of death: a
competing risk analysis of the melanoma in Southern Sweden cohort, J.
Intern. Med. 280 (4) (2016) 375–387, http://dx.doi.org/10.1111/joim.12496,
2016.
[55] E. McLafferty, C. Hendry, F. Alistair, The integumentary system: anatomy,
physiology and function of skin, Nurs. Stand. 27 (3) (2012) 35–42, http://dx.
doi.org/10.7748/ns2012.10.27.7.35.c9358.
[56] A. Slominski, D.J. Tobin, S. Shibahara, J. Wortsman, Melanin pigmentation in
mammalian skin and its hormonal regulation, Physiol. Rev. 84 (4) (2004)
1155–1228, http://dx.doi.org/10.1152/physrev.00044.2003.
[57] J.Y. Lin, D.E. Fisher, Melanocyte biology and skin pigmentation, Nature 445
(7130) (2007) 843–850, http://dx.doi.org/10.1038/nature05660.
[58] L.R. Sklar, F. Almutawa, H.W. Lim, I. Hamzavi, Effects of ultraviolet radiation,
visible light, and infrared radiation on erythema and pigmentation: a
review, Photochem. Photobiol. Sci. 12 (1) (2013) 54–64, http://dx.doi.org/10.
1039/c2pp25152c.
[59] G. Rivera-Gonzalez, B. Shook, V. Horsley, Adipocytes in skin health and
disease, Cold Spring Harb. Perspect. Med. 4 (3) (2014), http://dx.doi.org/10.
1101/cshperspect.a015271.
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
[60] I.L. Kruglikov, P.E. Scherer, Dermal adipocytes: from irrelevance to
metabolic targets? Trends Endocrinol. Metab. 27 (1) (2016) 1–10, http://dx.
doi.org/10.1016/j.tem.2015.11.002.
[61] T. Passeron, J. Krutmann, M.L. Andersen, R. Katta, C.C. Zouboulis, Clinical and
biological impact of the exposome on the skin, J. Eur. Acad. Dermatol.
Venereol. 34 (2020) 4–25, http://dx.doi.org/10.1111/jdv.16614.
[62] E. Dupont, J. Gomez, D. Bilodeau, Beyond UV radiation: a skin under
challenge, Int. J. Cosmet. Sci. 35 (3) (2013) 224–232, http://dx.doi.org/10.
1111/ics.12036.
[63] B.H. Mahmoud, C.L. Hexsel, I.H. Hamzavi, H.W. Lim, Effects of visible light on
the skin, Photochem. Photobiol. 84 (2) (2008) 450–462, http://dx.doi.org/10.
1111/j.1751-1097.2007.00286.x.
[64] J. D’Orazio, S. Jarrett, A. Amaro-Ortiz, T. Scott, UV radiation and the skin, Int.
J. Mol. Sci. 14 (6) (2013) 12222–12248, http://dx.doi.org/10.3390/
ijms140612222.
[65] M. Clement, G. Daniel, M. Trelles, Optimising the design of a broad-band
light source for the treatment of skin, J. Cosmet. Laser Ther. 7 (3-4) (2005)
177–189, http://dx.doi.org/10.1080/14764170500344575.
[66] C. Ash, M. Dubec, K. Donne, T. Bashford, Effect of wavelength and beam
width on penetration in light-tissue interaction using computational
methods, Lasers Med. Sci. 32 (8) (2017) 1909–1918, http://dx.doi.org/10.
1007/s10103-017-2317-4.
[67] A.J. Ridley, J.R. Whiteside, T.J. McMillan, S.L. Allinson, Cellular and
sub-cellular responses to UVA in relation to carcinogenesis, Int. J. Radiat.
Biol. 85 (3) (2009) 177–195, http://dx.doi.org/10.1080/
09553000902740150.
[68] R.M. Brand, P. Wipf, A. Durham, M.W. Epperly, J.S. Greenberger, L.D. Falo Jr,
Targeting mitochondrial oxidative stress to mitigate UV-induced skin
damage, Front. Pharmacol. 9 (2018) 920, http://dx.doi.org/10.3389/fphar.
2018.00920.
[69] L.H.F. Mullenders, Solar UV damage to cellular DNA: from mechanisms to
biological effects, Photochem. Photobiol. Sci. 17 (12) (2018) 1842–1852,
http://dx.doi.org/10.1039/c8pp00182k.
[70] C. Skobowiat, A.T. Slominski, UVB activates hypothalamic-pituitary-adrenal
axis in C57BL/6 mice, J. Invest. Dermatol. 135 (6) (2015) 1638–1648, http://
dx.doi.org/10.1038/jid.2014.450.
[71] I. Albers, E. Zernickel, M. Stern, M. Broja, H.L. Busch, C. Heiss, V. Grotheer, J.
Windolf, C.V. Suschek, Blue light (lambda=453nm) nitric oxide dependently
induces beta-endorphin production of human skin keratinocytes in-vitro
and increases systemic beta-endorphin levels in humans in-vivo, Free Radic.
Biol. Med. 145 (2019) 78–86, http://dx.doi.org/10.1016/j.freeradbiomed.
2019.09.022.
[72] M.F. Holick, Ultraviolet B radiation: the vitamin d connection, Adv. Exp. Med.
Biol. 996 (2017) 137–154, http://dx.doi.org/10.1007/978-3-319-56017-5 12.
[73] J. Liebmann, M. Born, V. Kolb-Bachofen, Blue-light irradiation regulates
proliferation and differentiation in human skin cells, J. Invest. Dermatol. 130
(1) (2010) 259–269, http://dx.doi.org/10.1038/jid.2009.194.
[74] S. Buscone, A.N. Mardaryev, B. Raafs, J.W. Bikker, C. Sticht, N. Gretz, N. Farjo,
N.E. Uzunbajakava, N.V. Botchkareva, A new path in defining light
parameters for hair growth: discovery and modulation of photoreceptors in
human hair follicle, Lasers Surg. Med. 49 (7) (2017) 705–718, http://dx.doi.
org/10.1002/lsm.22673.
[75] H.J. Kim, M.S. Choi, I.H. Bae, J.Y. Jung, E.D. Son, T.R. Lee, D.W. Shin, Short
wavelength visible light suppresses innate immunity-related responses by
modulating protein S-nitrosylation in keratinocytes, J. Invest. Dermatol. 136
(3) (2016) 727–731, http://dx.doi.org/10.1016/j.jid.2015.12.004.
[76] P.S. Oh, H. Hwang, H.S. Jeong, J. Kwon, H.S. Kim, M. Kim, S. Lim, M.H. Sohn,
H.J. Jeong, Blue light emitting diode induces apoptosis in lymphoid cells by
stimulating autophagy, Int. J. Biochem. Cell Biol. 70 (2016) 13–22, http://dx.
doi.org/10.1016/j.biocel.2015.11.004.
[77] G. Sikka, G.P. Hussmann, D. Pandey, S. Cao, D. Hori, J.T. Park, J. Steppan, J.H.
Kim, V. Barodka, A.C. Myers, L. Santhanam, D. Nyhan, M.K. Halushka, R.C.
Koehler, S.H. Snyder, L.A. Shimoda, D.E. Berkowitz, Melanopsin mediates
light-dependent relaxation in blood vessels, Proc. Natl. Acad. Sci. U. S. A. 111
(50) (2014) 17977–17982, http://dx.doi.org/10.1073/pnas.1420258111.
[78] H.J. Kim, E.D. Son, J.Y. Jung, H. Choi, T.R. Lee, D.W. Shin, Violet light down-
regulates the expression of specific differentiation markers through
rhodopsin in normal human epidermal keratinocytes, PLoS One 8 (9) (2013),
8, http://dx.doi.org/10.1371/journal.pone.007367, e73678.
[79] M.H. Catao, R.O. Costa, C.F. Nonaka, R.L. Junior, I.R. Costa, Green LED light has
anti-inflammatory effects on burns in rats, Burns 42 (2) (2016) 392–396,
http://dx.doi.org/10.1016/j.burns.2015.07.003.
[80] T.M.S. Simoes, J.A. Fernandes Neto, T.K.B. de Oliveira, C.F.W. Nonaka, M.
Catao, Photobiomodulation of red and green lights in the repair process of
third-degree skin burns, Lasers Med. Sci. 35 (1) (2020) 51–61, http://dx.doi.
org/10.1007/s10103-019-02776-7, 2020.
[81] L. Chen, Z. Xu, M. Jiang, C. Zhang, X. Wang, L. Xiang, Light-emitting diode
585nm photomodulation inhibiting melanin synthesis and inducing
autophagy in human melanocytes, J. Dermatol. Sci. 89 (1) (2018) 11–18,
http://dx.doi.org/10.1016/j.jdermsci.2017.10.001.
[82] Y.J. Kim, H.J. Kim, H.L. Kim, H.J. Kim, H.S. Kim, T.R. Lee, D.W. Shin, Y.R. Seo, A
protective mechanism of visible red light in normal human dermal
fibroblasts: enhancement of GADD45A-mediated DNA repair activity, J.
Invest. Dermatol. 137 (2) (2017) 466–474, http://dx.doi.org/10.1016/j.jid.
2016.07.041.
15
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
[83] S. Rohringer, W. Holnthoner, S. Chaudary, P. Slezak, E. Priglinger, M. Strassl,
K. Pill, S. Muhleder, H. Redl, P. Dungel, The impact of wavelengths of LED
light-therapy on endothelial cells, Sci. Rep. 7 (1) (2017) 10700, http://dx.doi.
org/10.1038/s41598-017-11061-y.
[84] H. Ma, J.-P. Yang, R.K. Tan, H.-W. Lee, S.-K. Han, Effect of low-level laser
therapy on proliferation and collagen synthesis of human fibroblasts in
vitro, J. Wound Manag. Res. 14 (1) (2018) 1–6, http://dx.doi.org/10.22467/
jwmr.2018.00283.
[85] D.R. Opel, E. Hagstrom, A.K. Pace, K. Sisto, S.A. Hirano-Ali, S. Desai, J. Swan,
Light- emitting diodes: a brief review and clinical experience, J. Clin.
Aesthet. Dermatol. 8 (6) (2015) 36–44.
[86] H. Serrage, V. Heiskanen, W.M. Palin, P.R. Cooper, M.R. Milward, M. Hadis,
M.R. Hamblin, Under the spotlight: mechanisms of photobiomodulation
concentrating on blue and green light, Photochem. Photobiol. Sci. 18 (8)
(2019) 1877–1909, http://dx.doi.org/10.1039/c9pp00089e.
[87] C. Mignon, N.E. Uzunbajakava, B. Raafs, N.V. Botchkareva, D.J. Tobin,
Photobiomodulation of human dermal fibroblasts in vitro: decisive role of
cell culture conditions and treatment protocols on experimental outcome,
Sci. Rep. 7 (1) (2017) 2797, http://dx.doi.org/10.1038/s41598-017-02802-0.
[88] A. Slominski, J. Wortsman, Neuroendocrinology of the skin, Endocr. Rev. 21
(5) (2000) 457–487, http://dx.doi.org/10.1210/edrv.21.5.0410.
[89] A.T. Slominski, M.A. Zmijewski, C. Skobowiat, B. Zbytek, R.M. Slominski, J.D.
Steketee, Sensing the environment: regulation of local and global
homeostasis by the skin’s neuroendocrine system, Adv. Anat. Embryol. Cell
Biol. 212 (vii) (2012) 1–115, http://dx.doi.org/10.1007/978-3-642-19683-6
1.
[90] D. Raj, D.E. Brash, D. Grossman, Keratinocyte apoptosis in epidermal
development and disease, J. Invest. Dermatol. 126 (2) (2006) 243–257,
http://dx.doi.org/10.1038/sj.jid.5700008.
[91] A. Costanzo, F. Fausti, G. Spallone, F. Moretti, A. Narcisi, E. Botti, Programmed
cell death in the skin, Int. J. Dev. Biol. 59 (1-3) (2015) 73–78, http://dx.doi.
org/10.1387/ijdb.150050ac.
[92] D. Mohania, S. Chandel, P. Kumar, V. Verma, K. Digvijay, D. Tripathi, K.
Choudhury, S.K. Mitten, D. Shah, Ultraviolet radiations: skin
defense-damage mechanism, Adv. Exp. Med. Biol. 996 (2017) 71–87, http://
dx.doi.org/10.1007/978-3-319-56017-5 7.
[93] P. Dakup, S. Gaddameedhi, Impact of the circadian clock on UV-induced
DNA damage response and photocarcinogenesis, Photochem. Photobiol. 93
(1) (2017) 296–303, http://dx.doi.org/10.1111/php.12662.
[94] M. Rinnerthaler, J. Bischof, M.K. Streubel, A. Trost, K. Richter, Oxidative
stress in aging human skin, Biomolecules 5 (2) (2015) 545–589, http://dx.
doi.org/10.3390/biom5020545.
[95] T.G. Polefka, T.A. Meyer, Cutaneous oxidative stress and aging, in: M.A.
Farage, K.W. Miller, H.I. Maibach (Eds.), Textbook of Aging Skin., Springer,
Berlin Heidelberg, Berlin, Heidelberg, 2016, pp. 651–676, http://dx.doi.org/
10.1007/978-3-662-47398-6 123.
[96] H. Wang, E.Q. van Spyk, M. Geyfman, M.L. Salmans, V. Kumar, A. Ihler, N.
Ning, J.S. Takahashi, B. Andersen, Time-restricted feeding shifts the skin
circadian clock and alters UVB-induced DNA damage, Cell Rep. 20 (5) (2017)
1061–1072, http://dx.doi.org/10.1016/j.celrep.2017.07.022.
[97] L.V.M. de Assis, M.N. Moraes, A.M.L. Castrucci, The molecular clock in the
skin, its functionality, and how it is disrupted in cutaneous melanoma: a
new pharmacological target? Cell. Mol. Life Sci. 76 (19) (2019) 3801–3826,
http://dx.doi.org/10.1007/s00018-019-03183-5.
[98] P.S. Welz, V.M. Zinna, A. Symeonidi, K.B. Koronowski, K. Kinouchi, J.G. Smith,
I.M. Guillén, A. Castellanos, S. Furrow, F. Aragón, G. Crainiciuc, N. Prats, J.M.
Caballero, A. Hidalgo, P. Sassone-Corsi, S.A. Benitah, BMAL1-driven tissue
clocks respond independently to light to maintain homeostasis, Cell 177 (6)
(2019) 1436–1447, http://dx.doi.org/10.1016/j.cell.2019.05.009.
[99] W. Schlosser, T. Schmidt-Kaler, E.F. Milone, W. Schlosser, T. Schmidt-Kaler,
E.F. Milone, Atmospheric effects on starlight and sunlight, in: Challenges
of.Astronomy, Springer, Berlin, 1991, pp. 98–105, http://dx.doi.org/10.1007/
978-1-4612-4434-9 19.
[100] M. Bohm, I. Holmer, H. Nilsson, O. Noren, Thermal effect of glazing in
driver’s cabs: evaluation of the impact of different types of glazing on the
thermal comfort, Semant. Sch.- Environ. Sci. (2002),
https://www.semanticscholar.org/paper/Thermal-effect-of-glazing-in-
driver’s-cabs-%3A-of-of-Bohm-
Holmér/90aaa26b5bc4f41658d020104a95662635619841#citing-papers.
[101] A. Hanafi, T. Gharbi, J.-Y. Cornu, In vivo measurement of lower back
deformations with Fourier-transform profilometry, Appl. Opt. 44 (2005)
2266–2273, http://dx.doi.org/10.1364/AO.44.002266.
[102] R. Anderson, J.A. Parrish, The optics of human skin, J. Invest. Dermatol. 77
(1981) 13–19, http://dx.doi.org/10.1111/1523-1747.ep12479191.
[103] P. Schroeder, C. Calles, T. Benesova, F. Macaluso, J. Krutmann,
Photoprotection beyond ultraviolet radiation – effective sun protection has
to include protection against infrared A radiation-induced skin damage,
Skin Pharmacol. Physiol. 23 (2010) 15–17.
[104] Scenihr, Scientific Committee on Emerging and Newly Identified Health
Risks SCENIHR Health Effects of Artificial Light, Report, 2012, http://dx.doi.
org/10.2772/8624.
[105] V.V. Barun, A.P. Ivanov, A.V. Volotovskaya, Absorption spectra and light
penetration depth of normal and pathologically altered human skin, J. Appl.
Spectrosc. 74 (2007) 430–439.
[106] R. Henderson, K. Schulmeister, Laser Safety, CRC Press, Boca Raton, 2004, pp.
474, http://dx.doi.org/10.1201/9781420034042.
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
[107] J. Leff, N.I. Krinsky, A mutagenic effect of visible light mediated by
endogenous pigments in Euglena gracilis, Science 158 (3806) (1967)
1332–1335, http://dx.doi.org/10.1126/science.158.3806.1332.
[108] G.P. Pfeifer, Y.-H. You, A. Besaratinia, Mutations induced by ultraviolet light,
Mutat. Res. Mol. Mech. Mutagen. 571 (2005) 19–31, http://dx.doi.org/10.
1016/j.mrfmmm.2004.06.057.
[109] G.P. Pfeifer, A. Besaratinia, UV wavelength-dependent DNA damage and
human non- melanoma and melanoma skin cancer, Photochem. Photobiol.
Sci. 11 (2012) 90–97, http://dx.doi.org/10.1039/C1PP05144J.
[110] A. Deaton, A. Bird, CpG islands and the regulation of transcription, Genes
Dev. 25 (2011) 1010–1022, http://dx.doi.org/10.1101/gad.2037511.1010.
[111] J. Cadet, E. Sage, T. Douki, Ultraviolet radiation-mediated damage to cellular
DNA, Mutat. Res. – Fundam. Mol. Mech. Mutagen. 571 (1-2) (2005) 3–17,
http://dx.doi.org/10.1016/j.mrfmmm.2004.09.012.
[112] J. Li, T. Uchida, T. Todo, T. Kitagawa, Similarities and differences between
cyclobutane pyrimidine dimer photolyase and (6-4) photolyase as revealed
by resonance Raman spectroscopy: electron transfer from the FAD cofactor
to ultraviolet-damaged DNA, J. Biol. Chem. 281 (35) (2006) 25551–25559,
http://dx.doi.org/10.1074/jbc.M604483200.
[113] T.T. Tasso, J.C. Schlothauer, H.C. Junqueira, T.A. Matias, K. Araki, É. Liandra-
Salvador, F.C.T. Antonio, P. Homem-De-Mello, M.S. Baptista, Photobleaching
efficiency parallels the enhancement of membrane damage for
porphyrazine photosensitizers, J. Am. Chem. Soc. 141 (2019) 15547–15556,
http://dx.doi.org/10.1021/jacs.9b05991.
[114] M.S. Baptista, J. Cadet, P. Di Mascio, A.A. Ghogare, A. Greer, M.R. Hamblin, C.
Lorente, S.C. Nunez, M.S. Ribeiro, A.H. Thomas, M. Vignoni, T.M. Yoshimura,
Type I and type II photosensitized oxidation reactions: guidelines and
mechanistic pathways, Photochem. Photobiol. 93 (2017) 912–919, http://dx.
doi.org/10.1111/php.12716.
[115] I.O.L. Bacellar, M.C. Oliveira, L.S. Dantas, E.B. Costa, H.C. Junqueira, W.K.
Martins, A.M. Durantini, G. Cosa, P. Di Mascio, M. Wainwright, R. Miotto,
R.M. Cordeiro, S. Miyamoto, M.S. Baptista, Photosensitized membrane
permeabilization requires contact- dependent reactions between
photosensitizer and lipids, J. Am. Chem. Soc. 140 (30) (2018) 9606–9615,
http://dx.doi.org/10.1021/jacs.8b05014.
[116] J. Baier, T. Maisch, M. Maier, E. Engel, M. Landthaler, W. Bäumler, Singlet
oxygen generation by UVA light exposure of endogenous photosensitizers,
Biophys. J. 91 (2006) 1452–1459, http://dx.doi.org/10.1529/biophysj.106.
082388.
[117] G.T. Wondrak, M.K. Jacobson, E.L. Jacobson, Endogenous
UVA-photosensitizers: mediators of skin photodamage and novel targets for
skin photoprotection, Photochem. Photobiol. Sci. 5 (2006) 215–237, http://
dx.doi.org/10.1039/B504573H.
[118] Y. Miyachi, Photoaging from an oxidative standpoint, J. Dermatol. Sci. 9 (2)
(1995) 79–86, http://dx.doi.org/10.1016/0923-1811(94)00363-J.
[119] A.A. Gorman, I. Hamblett, M.A.J. Rodgers, Ergosterol (provitamin D2) triplet
state: an efficient sensitizer of singlet oxygen, O2(g), formation,
Photochem. Photobiol. 45 (2) (1987) 215–221, http://dx.doi.org/10.1111/j.
1751-1097.1987.tb05366.x.
[120] A.A. Gorman, I. Hamblett, C. Lambert, A.L. Prescott, A pulse radiolysis and
pulsed laser study of the vitamin D3 triplet state: lifetime, relaxation and
nonvertical excitation, Photochem. Photobiol. 51 (1) (1990) 29–35, http://
dx.doi.org/10.1111/j.1751-1097.1990.tb01680.x.
[121] E. Oliveros, F. Besançon, M. Boneva, B. Kräutler, A.M. Braun, Singlet oxygen
(1g) sensitization and quenching by vitamin B12 derivatives, J.
Photochem. Photobiol. B, Biol. 29 (1) (1995) 37–44, http://dx.doi.org/10.
1016/1011-1344(95)90249-X.
[122] A. Feis, B. Wegewijs, W. Gärtner, S.E. Braslavsky, Role of the triplet state in
retinal photoisomerization as studied by laser-induced optoacoustic
spectroscopy, J. Phys. Chem. B 101 (38) (1997) 7620–7627, http://dx.doi.org/
10.1021/jp970879d.
[123] K. Bhattacharyya, P.K. Das, Quantitative aspects of all-trans-retinol singlet
and triplet quenching by oxygen, Chem. Phys. Lett. 116 (4) (1985) 326–332,
http://dx.doi.org/10.1016/0009- 2614(85)80178-0.
[124] A.V. Silva, A. López-Sánchez, H.C. Junqueira, L. Rivas, M.S. Baptista, G.
Orellana, Riboflavin derivatives for enhanced photodynamic activity against
Leishmania parasites, Tetrahedron 71 (3) (2015) 457–462, http://dx.doi.org/
10.1016/j.tet.2014.11.072.
[125] E. Consiglieri, Q. Xu, M. Bregnhøj, M. Westberg, P.R. Ogilby, A. Losi, Single
mutation in a novel bacterial LOV protein yields a singlet oxygen generator,
Photochem. Photobiol. Sci. 18 (2019) 2657–2660, http://dx.doi.org/10.1039/
c9pp00328b.
[126] A.H. Thomas, C. Lorente, A.L. Capparelli, C.G. Martínez, A.M. Braun, E.
Oliveros, Singlet oxygen (1g) production by pterin derivatives in aqueous
solutions, Photochem. Photobiol. Sci. 2 (2003) 245–250, http://dx.doi.org/
10.1039/b209993d.
[127] S.M. Bishop, M. Malone, D. Phillips, A.W. Parker, M.C.R. Symons, Singlet
oxygen sensitisation by excited state DNA, J. Chem. Soc. Chem. Commun.
1994 (1994) 871–872, http://dx.doi.org/10.1039/C39940000871.
[128] K.K. Chin, C.C. Trevithick-Sutton, J. McCallum, S. Jockusch, N.J. Turro, J.C.
Scaiano, C.S. Foote, M.A. Garcia-Garibay, Quantitative determination of
singlet oxygen generated by excited state aromatic amino acids, proteins,
and immunoglobulins, J. Am. Chem. Soc. 52 (14) (2008) 7671–7679, http://
dx.doi.org/10.1021/ja800926v.
[129] S.Y. Egorov, A.A. Krasnovsky Jr, Laser-induced luminescence of singlet
molecular oxygen: generation by drugs and pigments of biological
16
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
importance, Proc. SPIE 1403, Laser Appl. Life Sci. (1991), http://dx.doi.org/
10.1117/12.57282.
[130] A.F. Uchoa, P.P. Knox, R. Turchielle, N.K. Seifullina, M.S. Baptista, Singlet
oxygen generation in the reaction centers of Rhodobacter sphaeroides, Eur.
Biophys. J. 37 (2008) 843–850, http://dx.doi.org/10.1007/s00249-008-0287-
y.
[131] M. Rózanowska, J. Wessels, M. Boulton, J.M. Burke, M.A.J. Rodgers, T.G.
Truscott, T. Sarna, Blue light-induced singlet oxygen generation by retinal
lipofuscin in non-polar media, Free Radic. Biol. Med. 24 (1998) 1107–1112,
http://dx.doi.org/10.1016/S0891- 5849(97)00395-X.
[132] J.L. Spudich, C.S. Yang, K.H. Jung, E.N. Spudich, Retinylidene proteins:
structures and functions from archaea to humans, Annu. Rev. Cell Dev. Biol.
16 (2000) 365–392, http://dx.doi.org/10.1146/annurev.cellbio.16.1.365.
[133] V.J. Kefalov, Rod and cone visual pigments and phototransduction through
pharmacological, genetic, and physiological approaches, J. Biol. Chem. 287
(3) (2012) 1635–1641, http://dx.doi.org/10.1074/jbc.R111.303008.
[134] A. Terakita, T. Nagata, Functional properties of opsins and their contribution
to light- sensing physiology, Zool. Sci. 31 (10) (2014) 653–659, http://dx.doi.
org/10.2108/zs140094.
[135] D. Shen, M. Jiang, W. Hao, L. Tao, M. Salazar, H.K. Fong, A human
opsin-related gene that encodes a retinaldehyde binding protein,
Biochemistry 33 (1994) 13117–13125, http://dx.doi.org/10.1021/
bi00248a022.
[136] M. Koyanagi, A. Terakita, K. Kubokawa, Y. Shichida, Amphioxus homologs of
Go- coupled rhodopsin and peropsin having 11-cis- and all-trans-retinals as
their chromophores, FEBS Lett. 531 (2002) 525–528, http://dx.doi.org/10.
1016/s0014-5793(02)03616-5.
[137] T. Okano, T. Yoshizawa, Y. Fukada, Pinopsin is a chicken pineal
photoreceptive molecule, Nature 372 (1994) 94–97, http://dx.doi.org/10.
1038/372094a0.
[138] M. Max, P.J. McKinnon, K.J. Seidenman, R.K. Barrett, M.L. Applebury, J.S.
Takahashi, R.F. Margolskee, Pineal opsin: a nonvisual opsin expressed in
chick pineal, Science 267 (1995) 1502–1506, http://dx.doi.org/10.1126/
science.7878470.
[139] S. Kawamura, S. Yokoyama, Expression of visual and nonvisual opsins in
American chameleon, Vis. Res. 37 (1997) 1867–1871, http://dx.doi.org/10.
1016/S0042-6989(96)00309-4.
[140] T. Yoshikawa, Y. Yashiro, T. Oishi, K. Kokame, Y. Fukada, Immunoreactivities
to rhodopsin and rod/cone transducin antisera in the retina, pineal complex
and deep brain of the bullfrog, Rana catesbeiana, Zool. Sci. 11 (5) (1994)
675–680.
[141] S. Yokoyama, H. Zhang, Cloning and characterization of the pineal
gland-specific opsin gene of marine lamprey (Petromyzon marinus), Gene
202 (1-2) (1997) 89–93, http://dx.doi.org/10.1016/s0378-1119(97)00458-
7.
[142] I. Provencio, G. Jiang, W.J. De Grip, W.P. Hayes, M.D. Rollag, Melanopsin: an
opsin in melanophores, brain, and eye, Proc. Natl. Acad. Sci. U. S. A. 95
(1998) 340–345, http://dx.doi.org/10.1073/pnas.95.1.340.
[143] I. Provencio, I.R. Rodriguez, G. Jiang, W.P. Hayes, E.F. Moreira, M.D. Rollag, A
novel human opsin in the inner retina, J. Neurosci. 20 (2000) 600–605,
http://dx.doi.org/10.1523/JNEUROSCI.20-02-00600.2000.
[144] S. Panda, I. Provencio, D.C. Tu, S.S. Pires, M.D. Rollag, A.M. Castrucci, M.T.
Pletcher, T.K. Sato, T. Wiltshire, M. Andahazy, S.A. Kay, R.N. Van Gelder, J.B.
Hogenesch, Melanopsin is required for non-image-forming photic responses
in blind mice, Science 301 (5632) (2003) 525–527, http://dx.doi.org/10.
1126/science.1086179.
[145] Y. Miyashita, T. Moriya, T. Kubota, K. Yamada, K. Asami, Expression of opsin
molecule in cultured murine melanocyte, J. Investig. Dermatol. Symp. Proc.
6 (2001) 54–57, http://dx.doi.org/10.1046/j.0022-202x.2001.00018.x.
[146] G.J. Lopes, C.C. Gois, L.H. Lima, A.M. Castrucci, Modulation of rhodopsin gene
expression and signaling mechanisms evoked by endothelins in goldfish and
murine pigment cell lines, Braz. J. Med. Biol. Res. 43 (2010) 828–836, http://
dx.doi.org/10.1590/s0100- 879x2010007500087.
[147] J. Bellingham, D. Whitmore, A.R. Philp, D.J. Wells, R.G. Foster, Zebrafish
melanopsin: isolation, tissue localisation and phylogenetic position, Brain
Res. Mol. Brain Res. 107 (2) (2002) 128–136, http://dx.doi.org/10.1016/
s0169-328x(02)00454-0.
[148] N. Oshima, Direct reception of light by chromatophores of lower
vertebrates, Pigment Cell Res. 14 (5) (2001) 312–319, http://dx.doi.org/10.
1034/j.1600-0749.2001.140502.x.
[149] M. Tsutsumi, K. Ikeyama, S. Denda, J. Nakanishi, S. Fuziwara, H. Aoki, M.
Denda, Expressions of rod and cone photoreceptor-like proteins in human
epidermis, Exp. Dermatol. 18 (6) (2009) 567–570, http://dx.doi.org/10.1111/
j.1600-0625.2009.00851.x.
[150] N.L. Wicks, J.W. Chan, J.A. Najera, J.M. Ciriello, E. Oancea, UVA
phototransduction drives early melanin synthesis in human melanocytes,
Curr. Biol. 21 (22) (2011) 1906–1911, http://dx.doi.org/10.1016/j.cub.2011.
09.047.
[151] M. Denda, S. Fuziwara, Visible radiation affects epidermal permeability
barrier recovery: selective effects of red and blue light, J. Invest. Dermatol.
28 (2008) 1335–1336, http://dx.doi.org/10.1038/sj.jid.5701168.
[152] D. Kojima, S. Mori, M. Torii, A. Wada, R. Morishita, Y. Fukada, UV-sensitive
photoreceptor protein OPN5 in humans and mice, PLoS One 6 (10) (2011),
http://dx.doi.org/10.1371/journal.pone.0026388, e26388.
[153] L.V.M. de Assis, M.N. Moraes, S.S. Cruz-Machado, A.M.L. Castrucci, The effect
of white light on normal and malignant murine melanocytes: A link between
L.V.M. de Assis, P.N. Tonolli, M.N. Moraes et al.
opsins, clock genes, and melanogenesis, Biochim. Biophys. Acta 1863 (6 Pt
A) (2016) 1119–1133, http://dx.doi.org/10.1016/j.bbamcr.2016.03.001.
[154] P.P. Toh, M. Bigliardi-Qi, A.M.Y. Yap, G. Sriram, O. Stelmashenko, P. Bigliardi,
Expression of peropsin in human skin is related to phototransduction of
violet light in keratinocytes, Exp. Dermatol. 25 (12) (2016) 1002–1005,
http://dx.doi.org/10.1111/exd.13226.
[155] Y. Lan, Y. Wang, H. Lu, Opsin 3 is a key regulator of ultraviolet A-induced
photoaging in human dermal fibroblast cells, Br. J. Dermatol. 182 (5) (2019)
1228–1244, http://dx.doi.org/10.1111/bjd.18410.
[156] J. Kusumoto, M. Takeo, K. Hashikawa, T. Komori, T. Tsuji, H. Terashi, S.
Sakakibara, OPN4 belongs to the photosensitive system of the human skin,
Genes Cells 25 (3) (2020) 215–225, http://dx.doi.org/10.1111/gtc.12751.
[157] G. Hinterhuber, K. Cauza, K. Brugger, R. Dingelmaier-Hovorka, R. Horvat, K.
Wolff, D. Foedinger, RPE65 of retinal pigment epithelium, a putative
receptor molecule for plasma retinol-binding protein, is expressed in
human keratinocytes, J. Invest. Dermatol. 122 (2) (2004) 406–413, http://dx.
doi.org/10.1046/j.0022-202X.2004.22216.x.
[158] Y. Shichida, T. Matsuyama, Evolution of opsins and phototransduction,
Philos. Trans. R. Soc. B Biol. Sci. 364 (1531) (2009) 2881–2895, http://dx.doi.
org/10.1098/rstb.2009.0051.
[159] R. Birge, Photophysics and molecular electronic applications of the
rhodopsins, Annu. Rev. Phys. Chem. 41 (1990) 683–733, doi:
10.1146/annurev.pc.41.10 0190.003343.
[160] D. Oesterhelt, W. Stoeckenius, Functions of a new photoreceptor membrane,
Proc. Natl. Acad. Sci. U. S. A. 70 (10) (1973) 2853–2857, http://dx.doi.org/10.
1073/pnas.70.10.2853.
[161] K. Inoue, T. Tsukamoto, Y. Sudo, Molecular and evolutionary aspects of
microbial sensory rhodopsins, Biochim. Biophys. Acta 1837 (5) (2014)
562–577, http://dx.doi.org/10.1016/j.bbabio.2013.05.005.
[162] M. Kurihara, Y. Sudo, Microbial rhodopsins: wide distribution, rich diversity
and great potential, Biophys. Physicobiol. 12 (2015) 121–129, http://dx.doi.
org/10.2142/biophysico.12.0 121.
[163] A. Cooper, Energy uptake in the first step of visual excitation, Nature 282
(5738) (1979) 531–533, http://dx.doi.org/10.1038/282531a0.
[164] E.A. Zhukovsky, D.D. Oprian, Effect of carboxylic acid side chains on the
absorption maximum of visual pigments, Science 246 (4932) (1989)
928–930, http://dx.doi.org/10.1126/science.2573154.
[165] Y. Shichida, H. Imai, Visual pigment: G-protein-coupled receptor for light
signals, Cell. Mol. Life Sci. 54 (12) (1998) 1299–1315, http://dx.doi.org/10.
1007/s000180050256.
[166] J.E. Kim, M.J. Tauber, R.A. Mathies, Wavelength dependent cis-trans
isomerization in vision, Biochemistry 40 (46) (2001) 13774–13778, http://
dx.doi.org/10.1021/bi0116137.
[167] R.W. Schoenlein, L.A. Peteanu, R.A. Mathies, C.V. Shank, The first step in
vision: femtosecond isomerization of rhodopsin, Science 254 (5030) (1991)
412–415, http://dx.doi.org/10.1126/science.1925597.
[168] D. Polli, P. Altoè, O. Weingart, K.M. Spillane, C. Manzoni, D. Brida, G.
Tomasello, G. Orlandi, P. Kukura, R.A. Mathies, M. Garavelli, G. Cerullo,
Conical intersection dynamics of the primary photoisomerization event in
vision, Nature 467 (2010) 440–443, http://dx.doi.org/10.1038/nature09346.
[169] G. Moiseyev, Y. Chen, Y. Takahashi, B.X. Wu, J.X. Ma, RPE65 is the
isomerohydrolase in the retinoid visual cycle, Proc. Natl. Acad. Sci. U. S. A.
102 (35) (2005) 12413–12418, http://dx.doi.org/10.1073/pnas.0503460102.
[170] T. Matsuyama, T. Yamashita, Y. Imamoto, Y. Shichida, Photochemical
properties of mammalian melanopsin, Biochemistry 51 (27) (2012)
5454–5462, http://dx.doi.org/10.1021/bi3004999.
[171] M. Koyanagi, K. Kubokawa, H. Tsukamoto, Y. Shichida, A. Terakita,
Cephalochordate melanopsin: evolutionary linkage between invertebrate
visual cells and vertebrate photosensitive retinal ganglion cells, Curr. Biol.
15 (11) (2005) 1065–1069, http://dx.doi.org/10.1016/j.cub.2005.04.063.
[172] T. Sugihara, T. Nagata, B. Mason, M. Koyanagi, A. Terakita, Absorption
characteristics of vertebrate non-visual opsin, Opn3, PLoS One 11 (8) (2016),
http://dx.doi.org/10.1371/journal.pone.0161215, e0161215.
[173] S.G. Solomon, P. Lennie, The machinery of colour vision, Nat. Rev. Neurosci.
8 (4) (2007) 276–286, http://dx.doi.org/10.1038/nrn2094.
[174] N.W. Bellono, E. Oancea, UV light phototransduction depolarizes human
melanocytes, Channels 7 (2013) 243–248, http://dx.doi.org/10.4161/chan.
25322.
[175] N.W. Bellono, L.G. Kammel, A.L. Zimmerman, E. Oancea, UV light
phototransduction activates transient receptor potential A1 ion channels in
human melanocytes, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 2383–2388,
http://dx.doi.org/10.1073/pnas.1215555110.
17
Journal of Photochemistry and Photobiology C: Photochemistry Reviews 47 (2021) 100403
[176] W.L. Shen, Y. Kwon, A.A. Adegbola, J. Luo, A. Chess, C. Montell, Function of
rhodopsin in temperature discrimination in Drosophila, Science 331 (6022)
(2011) 1333–1336, http://dx.doi.org/10.1126/science.1198904.
[177] H.B. Barlow, The thermal limit to seeing, Nature 334 (1988) 296–297, http://
dx.doi.org/10.1038/334296a0.
[178] R.B. Barlow, R.R. Birge, E. Kaplan, J.R. Tallent, On the molecular origin of
photoreceptor noise, Nature 366 (1993) 64–66, http://dx.doi.org/10.1038/
366064a0, 1993.
[179] Y. Guo, H.P. Hendrickson, P.E. Videla, Y.-N. Chen, J. Ho, S. Sekharan, V.S.
Batista, J.C. Tully, E.C.Y. Yan, Probing the remarkable thermal kinetics of
visual rhodopsin with E181Q and S186A mutants, J. Chem. Phys. 146 (2017)
215104, http://dx.doi.org/10.1063/1.4984818.
[180] T. Sokabe, H.C. Chen, J. Luo, C. Montell, A switch in thermal preference in
Drosophila larvae depends on multiple rhodopsins, Cell Rep. 17 (2) (2016)
336–344, http://dx.doi.org/10.1016/j.celrep.2016.09.028.
[181] S. Pérez-Cerezales, S. Boryshpolets, O. Afanzar, A. Brandis, R. Nevo, V. Kiss,
M. Eisenbach, Involvement of opsins in mammalian sperm thermotaxis, Sci.
Rep. 5 (2015) 16146, http://dx.doi.org/10.1038/srep16146.
[182] D. Roy, K. Levi, V. Kiss, R. Nevo, M. Eisenbach, Rhodopsin and melanopsin
coexist in mammalian sperm cell and activate different signaling pathways
for thermotaxis, Sci. Rep. 10 (1) (2020) 112, http://dx.doi.org/10.1038/
s41598-019-56846-5.
[183] M.N. Moraes, L.V.M. de Assis, K.K. Magalhães-Marques, M.O. Poletini,
L.H.R.G. de Lima, A.M.L. Castrucci, Melanopsin, a canonical light receptor,
mediates thermal activation of clock genes, Sci. Rep. 7 (1) (2017) 13977,
http://dx.doi.org/10.1038/s41598-017-13939-3.
[184] N.W. Bellono, J.A. Najera, E. Oancea, UV light activates a Galphaq/11-coupled
phototransduction pathway in human melanocytes, J. Gen. Physiol. 143
(2014) 203–214, http://dx.doi.org/10.1085/jgp.201311094.
[185] T. Sugiyama, H. Suzuki, T. Takahashi, Light-induced rapid Ca2+ response and
MAPK phosphorylation in the cells heterologously expressing human OPN5,
Sci. Rep. 4 (2014) 5352, http://dx.doi.org/10.1038/srep05352.
[186] L.V.M. de Assis, M.N. Moraes, A.M.L. Castrucci, Heat shock antagonizes UVA-
induced responses in murine melanocytes and melanoma cells: an
unexpected interaction, Photochem. Photobiol. Sci. 16 (2017) 633–648,
http://dx.doi.org/10.1039/c6pp00330c.
[187] Q.-M. Hu, W.-J. Yi, M.-Y. Su, S. Jiang, S.-Z. Xu, T.-C. Lei, Induction of retinal-
dependent calcium influx in human melanocytes by UVA or UVB radiation
contributes to the stimulation of melanosome transfer, Cell Prolif. 50 (2017),
http://dx.doi.org/10.1111/cpr.12372, e12372.
[188] I. Castellano-Pellicena, N.E. Uzunbajakava, C. Mignon, B. Raafs, V.A.
Botchkarev, M.J. Thornton, Does blue light restore human epidermal barrier
function via activation of opsin during cutaneous wound healing? Lasers
Surg, Med. 51 (4) (2019) 370–382, http://dx.doi.org/10.1002/lsm.23015.
[189] Y. Lan, Y. Wang, H. Lu, Opsin 3 is a key regulator of ultraviolet A-induced
photoaging in human dermal fibroblast cells, Br. J. Dermatol. 182 (5) (2019)
1228–1244, http://dx.doi.org/10.1111/bjd.18410.
[190] Y. Wang, Y. Lan, H. Lu, Opsin3 downregulation induces apoptosis of human
epidermal 509 melanocytes via mitochondrial pathway, Photochem.
Photobiol. 96 (2020) 83–93, http://dx.doi.org/10.1111/php.13178.
[191] L.V.M. de Assis, D. Mendes, M.M. Silva, G.S. Kinker, I. Pereira-Lima, M.N.
Moraes, C.F.M. Menck, A.M.L. Castrucci, Melanopsin mediates
UVA-dependent modulation of proliferation, pigmentation, apoptosis, and
molecular clock in normal and malignant melanocytes, BBA – Mol. Cell. Res.
1867 (2020) 118789, http://dx.doi.org/10.1016/j.bbamcr.2020.118789.
[192] H. Dumbuya, S.Y. Hafez, E. Oancea, Cross talk between calcium and ROS
regulates the UVA-induced melanin response in human melanocytes, FASEB
J. 34 (9) (2020) 11605–11623, http://dx.doi.org/10.1096/fj.201903024R.
[193] E.D. Buhr, S. Vemaraju, N. Diaz, R.A. Lang, R.N. Van Gelder, Neuropsin (OPN5)
mediates local light-dependent induction of circadian clock genes and
circadian photoentrainment in exposed murine skin, Curr. Biol. 29 (20)
(2019) 3478–3487, http://dx.doi.org/10.1016/j.cub.2019.08.063.
[194] S.M. Fan, Y.T. Chang, C.L. Chen, W.H. Wang, M.K. Pan, W.P. Chen, W.Y. Huang,
Z. Xu, H.E. Huang, T. Chen, M.V. Plikus, S.K. Chen, S.J. Lin, External light
activates hair follicle stem cells through eyes via an ipRGC-SCN-sympathetic
neural pathway, Proc. Natl. Acad. Sci. U. S. A. 115 (29) (2018) E6880–e6889,
http://dx.doi.org/10.1073/pnas.1719548115.
[195] Y. Leung, D.P. Thakur, A.S. Gurav, S.H. Kim, A. Di Pizio, M.Y. Niv, C. Montell,
Functions of opsins in Drosophila taste, Curr. Biol. 30 (8) (2020) 1367–1379,
http://dx.doi.org/10.1016/j.cub.2020.01.068.
[196] M. Wehling, Rapid actions of aldosterone revisited: receptors in the
limelight, J. Steroid Biochem. Mol. Biol. 176 (2018) 94–98, http://dx.doi.org/
10.1016/j.jsbmb.2017.01.016.