Visual phototransduction

Visual phototransduction is the sensory

transduction of the visual system. It is a
process by which light is converted into
electrical signals in the rod cells, cone cells
and photosensitive ganglion cells of the retina
of the eye. This cycle was elucidated by
George Wald (1906–1997) for which he
received the Nobel Prize in 1967. It is so
called "Wald's Visual Cycle" after him.

The visual cycle is the biological conversion

of a photon into an electrical signal in the
retina. This process occurs via G-protein
coupled receptors called opsins which contain
the chromophore 11-cis retinal. 11-cis retinal
is covalently linked to the opsin receptor via
Schiff base forming retinylidene protein.
When struck by a photon, 11-cis retinal
undergoes photoisomerization to all-trans The Visual Cycle. hν = Incident photon
retinal which changes the conformation of the
opsin GPCR leading to signal transduction
cascades which causes closure of cyclic GMP-gated cation channel, and hyperpolarization of the photoreceptor cell.

Following isomerization and release from the opsin protein, all-trans retinal is reduced to all-trans retinol and travels back to the
retinal pigment epithelium to be "recharged". It is first esterified by lecithin retinol acyltransferase (LRAT) and then converted to
11-cis retinol by the isomerohydrolase RPE65. The isomerase activity of RPE65 has been shown; it is still uncertain whether it
also acts as hydrolase. Finally, it is oxidized to 11-cis retinal before traveling back to the rod outer segment where it is again
conjugated to an opsin to form new, functional visual pigment (rhodopsin).

Contents
Photoreceptors
Process
In the dark
In the light
Deactivation of the phototransduction cascade
Phototransduction in invertebrates
References
External links

Photoreceptors
The photoreceptor cells involved in vision are the rods and cones. These cells contain a chromophore (11-cis retinal, the aldehyde
of Vitamin A1 and light-absorbing portion) bound to cell membrane protein, opsin. Rods deal with low light level and do not
mediate color vision. Cones, on the other hand, can code the color of an image through comparison of the outputs of the three
different types of cones. Each cone type responds best to certain wavelengths, or colors, of light because each type has a slightly
different opsin. The three types of cones are L-cones, M-cones and S-cones that respond optimally to long wavelengths (reddish
color), medium wavelengths (greenish color), and short wavelengths (bluish color) respectively. Humans have a trichromatic
visual system consisting of three unique systems, rods, mid and long-wavelength sensitive (red and green) cones and short
wavelength sensitive (blue) cones.[1]

Process
To understand the photoreceptor's behaviour to light intensities, it is necessary to
understand the roles of different currents.

There is an ongoing outward potassium current through nongated K+-selective

channels. This outward current tends to hyperpolarize the photoreceptor at
around -70 mV (the equilibrium potential for K+).

There is also an inward sodium current carried by cGMP-gated sodium channels.

This so-called 'dark current' depolarizes the cell to around -40 mV. Note that this
is significantly more depolarized than most other neurons.

A high density of Na+-K+ pumps enables the photoreceptor to maintain a steady

The absorption of light leads to an
intracellular concentration of Na+ and K+.
isomeric change in the retinal
molecule.
In the dark
Photoreceptor cells are unusual cells in that they depolarize in response to absence of stimuli or scotopic conditions (darkness). In
photopic conditions (light), photoreceptors hyperpolarize to a potential of -60mV.

In the dark, cGMP levels are high and keep cGMP-gated sodium channels open allowing a steady inward current, called the dark
current. This dark current keeps the cell depolarized at about -40 mV, leading to glutamate release which inhibits excitation of
neurons.

The depolarization of the cell membrane in scotopic conditions opens voltage-gated calcium channels. An increased intracellular
concentration of Ca2+ causes vesicles containing glutamate, a neurotransmitter, to merge with the cell membrane, therefore
releasing glutamate into the synaptic cleft, an area between the end of one cell and the beginning of another neuron. Glutamate,
though usually excitatory, functions here as an inhibitory neurotransmitter.

In the cone pathway glutamate:

Hyperpolarizes on-center bipolar cells. Glutamate that is released from the photoreceptors in the dark binds to
metabotropic glutamate receptors (mGluR6), which, through a G-protein coupling mechanism, causes non-
specific cation channels in the cells to close, thus hyperpolarizing the bipolar cell.
Depolarizes off-center bipolar cells. Binding of glutamate to ionotropic glutamate receptors results in an inward
cation current that depolarizes the bipolar cell.

In the light
In summary: Light closes cGMP-gated sodium channels, reducing the influx of both Na+ and Ca2+ ions. Stopping the influx of
Na+ ions effectively switches off the dark current. Reducing this dark current causes the photoreceptor to hyperpolarise, which
reduces glutamate release which thus reduces the inhibition of retinal nerves, leading to excitation of these nerves. This reduced
Ca2+ influx during phototransduction enables deactivation and recovery from phototransduction, as discussed in Visual
phototransduction#Deactivation of the phototransduction cascade.

1. A light photon
interacts with the
retinal in a
photoreceptor cell.
The retinal
undergoes
isomerisation,
changing from the
11-cis to all-trans
configuration.
2. Opsin therefore
undergoes a
conformational
change to
metarhodopsin II.
Representation of molecular steps in photoactivation (modified from Leskov et al.,
3. Metarhodopsin II
activates a G 2000[2]). Depicted is an outer membrane disk in a rod. Step 1: Incident photon (hν) is
protein known as absorbed and activates a rhodopsin by conformational change in the disk membrane
transducin. This to R*. Step 2: Next, R* makes repeated contacts with transducin molecules, catalyzing
causes transducin its activation to G* by the release of bound GDP in exchange for cytoplasmic GTP,
to dissociate from
its bound GDP, and which expels its β and γ subunits. Step 3: G* binds inhibitory γ subunits of the
bind GTP, then the phosphodiesterase (PDE) activating its α and β subunits. Step 4: Activated PDE
alpha subunit of hydrolyzes cGMP. Step 5: Guanylyl cyclase (GC) synthesizes cGMP, the second
transducin messenger in the phototransduction cascade. Reduced levels of cytosolic cGMP
dissociates from the cause cyclic nucleotide gated channels to close preventing further influx of Na+ and
beta and gamma
subunits, with the Ca2+.
GTP still bound to
the alpha subunit.
4. The alpha subunit-GTP complex activates phosphodiesterase, also known as PDE6. It binds to one of two
regulatory subunits of PDE (which itself is a tetramer) and inhibits its activity.
5. PDE hydrolyzes cGMP, forming GMP. This lowers the intracellular concentration of cGMP and therefore the
sodium channels close.[3]
6. Closure of the sodium channels causes hyperpolarization of the cell due to the ongoing efflux of potassium ions.
7. Hyperpolarization of the cell causes voltage-gated calcium channels to close.
8. As the calcium level in the photoreceptor cell drops, the amount of the neurotransmitter glutamate that is
released by the cell also drops. This is because calcium is required for the glutamate-containing vesicles to fuse
with cell membrane and release their contents (see SNARE proteins).
9. A decrease in the amount of glutamate released by the photoreceptors causes depolarization of on-center bipolar
cells (rod and cone On bipolar cells) and hyperpolarization of cone off-center bipolar cells.

Deactivation of the phototransduction cascade

In light, low cGMP levels close Na+ and Ca2+ channels, reducing intracellular Na+ and Ca2+. During recovery (dark
adaptation), the low Ca2+ levels induce recovery (termination of the phototransduction cascade), as follows:

1. Low intracellular Ca2+ makes intracellular Ca-GCAP (Ca-Gunylate cyclase activating protein) dissociate into
Ca2+ and GCAP. The liberated GCAP ultimately restores depleted cGMP levels, which re-opens the cGMP-
gated cation channels (restoring dark current).
2. Low intracellular Ca2+ makes intracellular Ca-GAP (Ca-GTPase Accelerating Protein) dissociate into Ca2+ and
GAP. The liberated GAP deactivates activated-Transducin, terminating the phototransduction cascade (restoring
dark current).
 3. Low intracellular Ca2+ makes intracellular Ca-recoverin-RK dissociate into Ca2+ and recoverin and RK. The
liberated RK then phosphorylates the Metarhodopsin II, reducing its binding affinity for transducin. Arrestin then
completely deactivates the phosphorylated-metarhodopsin II, terminating the phototransduction cascade
(restoring dark current).
4. Low intracellular Ca2+ make the Ca2+/Calmodulin complex within the cGMP-gated cation channels more
sensitive to low cGMP levels (thereby, keeping the cGMP-gated cation channel open even at low cGMP levels,
restoring dark current)[4]
In more detail:

GTPase Accelerating Protein (GAP) interacts with the alpha subunit of transducin, and causes it to hydrolyse its bound GTP to
GDP, and thus halts the action of phosphodiesterase, stopping the transformation of cGMP to GMP.

In other words: Guanylate Cyclase Activating Protein (GCAP) is a calcium binding protein, and as the calcium levels in the cell
have decreased, GCAP dissociates from its bound calcium ions, and interacts with Guanylate Cyclase, activating it. Guanylate
Cyclase then proceeds to transform GTP to cGMP, replenishing the cell's cGMP levels and thus reopening the sodium channels
that were closed during phototransduction.

Finally, Metarhodopsin II is deactivated. Recoverin, another calcium binding protein, is normally bound to Rhodopsin Kinase
when calcium is present. When the calcium levels fall during phototransduction, the calcium dissociates from recoverin, and
rhodopsin kinase is released, when it (what?) proceeds to phosphorylate metarhodopsin II, which decreases its affinity for
transducin. Finally, arrestin, another protein, binds the phosphorylated metarhodopsin II, completely deactivating it. Thus, finally,
phototransduction is deactivated, and the dark current and glutamate release is restored. It is this pathway, where Metarhodopsin
II is phosphorylated and bound to arrestin and thus deactivated, which is thought to be responsible for the S2 component of dark
adaptation. The S2 component represents a linear section of the dark adaptation function present at the beginning of dark
adaptation for all bleaching intensities.

All-trans retinal is transported to the pigment epithelial cells to be reduced to all-trans retinol, the precursor to 11-cis retinal. This
is then transported back to the rods. All-trans retinal cannot be synthesised by humans and must be supplied by vitamin A in the
diet. Deficiency of all-trans retinal can lead to night blindness. This is part of the bleach and recycle process of retinoids in the
photoreceptors and retinal pigment epithelium.

Phototransduction in invertebrates
Phototransduction process in invertebrates like the fruit fly is different from the vertebrates. PI(4,5)P2 cycle underlies the
phototransduction process. Here, light induces the conformational change into Rhodopsin and converts it into meta-rhodopsin.
This helps in dissociation of G -protein complex. Alpha sub-unit of this complex activates the PLC enzyme (PLC-beta) which
hydrolyze the PIP2 into DAG. This hydrolysis leads to opening of TRP channels and influx of calcium.

References
1. Ebrey, Thomas; Koutalos, Yiannis (January 2001). "Vertebrate Photoreceptors". Progress in Retinal and Eye
Research. 20 (1): 49–94. doi:10.1016/S1350-9462(00)00014-8 (https://doi.org/10.1016%2FS1350-9462%2800%
2900014-8). PMID 11070368 (https://www.ncbi.nlm.nih.gov/pubmed/11070368).
2. Leskov, Ilya; Klenchin, Handy, Whitlock, Govardovskii, Bownds, Lamb, Pugh, Arshavsky (September 2000). "The
Gain of Rod Phototransduction: Reconciliation of Biochemical and Electrophysiological Measurements". Neuron.
27 (3): 525–537. doi:10.1016/S0896-6273(00)00063-5 (https://doi.org/10.1016%2FS0896-6273%2800%2900063
-5).
3. Arshavsky, Vadim Y.; Lamb, Trevor D.; Pugh, Edward N. (2002). "G Proteins and Phototransduction". Annual
Review of Physiology. 64 (1): 153–187. doi:10.1146/annurev.physiol.64.082701.102229 (https://doi.org/10.114
6%2Fannurev.physiol.64.082701.102229). PMID 11826267 (https://www.ncbi.nlm.nih.gov/pubmed/11826267).
 4. Hsu, Yi-Te; Molday, Robert S. (1993). "Modulation of the CGMP-gated channel of rod photoreceptor cells by
calmodulin". Nature. 361 (6407): 76–79. Bibcode:1993Natur.361...76H (https://ui.adsabs.harvard.edu/abs/1993N
atur.361...76H). doi:10.1038/361076a0 (https://doi.org/10.1038%2F361076a0). PMID 7678445 (https://www.ncbi.
nlm.nih.gov/pubmed/7678445).

Moiseyev G, Chen Y, Takahashi Y, Wu BX, Ma JX. RPE65 is the isomerohydrolase in the retinoid visual cycle.
Proc. Natl. Acad. Sci. 2005 Article (http://www.pnas.org/cgi/content/full/102/35/12413).
Jin M, Li S, Moghrabi WN, Sun H, Travis GH. Rpe65 is the retinoid isomerase in bovine retinal pigment
epithelium. Cell. 2005 Article (https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed).

External links
Visual pigments and visual transduction at med.utah.edu (http://webvision.med.utah.edu/)
Transduction of Light Prezi (https://prezi.com/view/zsG4HF8oit2XgZlla33P/)
A General Overview on Visual Perception at brynmawr.edu (http://serendip.brynmawr.edu/bb/neuro/neuro00/web
1/Patel.html)
Phototransduction (https://meshb.nlm.nih.gov/record/ui?name=Phototransduction) at the US National Library of
Medicine Medical Subject Headings (MeSH)

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