REVIEWS

Transient receptor potential channels

as therapeutic targets
Magdalene M. Moran*, Michael Allen McAlexander‡, Tamás Bíró§ and
Arpad Szallasi||¶
Abstract | Transient receptor potential (TRP) cation channels have been among the most
aggressively pursued drug targets over the past few years. Although the initial focus of
research was on TRP channels that are expressed by nociceptors, there has been an upsurge
in the amount of research that implicates TRP channels in other areas of physiology and
pathophysiology, including the skin, bladder and pulmonary systems. In addition, mutations
in genes encoding TRP channels are the cause of several inherited diseases that affect a
variety of systems including the renal, skeletal and nervous system. This Review focuses on
recent developments in the TRP channel-related field, and highlights potential opportunities
for therapeutic intervention.

*Hydra Biosciences,
790 Memorial Drive,
Cambridge, Massachusetts
02139, USA.
‡
Neuronal Targets Discovery
Performance Unit,
GlaxoSmithKline
Pharmaceuticals,King of
Prussia, Pennsylvania, USA.
§
Department of Physiology,
Research Center for
Molecular Medicine,
University of Debrecen, 4032
Debrecen, Hungary.
||
Department of Pathology,
Monmouth Medical Center,
300 Second Avenue,
Long Branch,
New Jersey 07740, USA.
¶
Drexel University College
of Medicine, Philadelphia,
Pennsylvania 19102, USA.
Correspondence to A.S. 
e‑mail: aszallasi@sbhcs.com
doi:10.1038/nrd3456
Transient receptor potential (TRP) channels (BOX 1; FIG. 1)
are being ardently pursued as targets for drug discovery.
There are several factors that make TRP cation channels
appealing as drug targets. First, although ion channels
have been successful drug targets, achieving subtype-
selectivity has always been a major challenge, particu-
larly with voltage-gated sodium and calcium channels.
As members of the TRP family of channels do not share
much homology with one another, the identification of
subtype-selective compounds is likely to be more attain-
able. Second, TRP channels act as integrators of several
well-described signalling systems, including those that
are mediated by cell surface receptors (for example,
G protein-coupled receptors (GPCRs) and growth fac-
tor receptors). Third, mutations in many of the genes
that encode TRP channels are sufficient to cause disease
in humans.
Pioneering research in the field of pain has established
that a subset of TRP channels (those that are activated
by temperatures; the so-called thermoTRP channels)
are capable of initiating sensory nerve impulses fol-
lowing the detection of chemical and thermal stimuli
(reviewed in REFS 1,2). Although pain is currently the
most advanced TRP channel-related field, an increasing
number of gene deletion studies in animals and genetic
association studies in humans have demonstrated that
the pathophysiological roles of TRP channels extend well
beyond the sensory nervous system (reviewed in REF. 3).
Indeed, even broadly classifying TRP channels as sensors
of environmental cues understates the diversity of their
function. In fact, many TRP channels are activated by
second messenger signalling cascades that are initiated
by receptor activation, and some TRP channels function
on intracellular membranes3.
TRP channels are associated with several pathophysi-
ological processes, which include (but are not limited to)
pain, respiratory reflex hypersensitivity, cardiac hyper-
trophy and ischaemic cell death3. In addition, several
gene association studies in humans have indicated that
single-nucleotide polymorphisms (SNPs) in the cod-
ing regions and/or promoters of genes that encode TRP
channels are either associated with an increased risk of
multifactorial diseases or they appear to be causative
factors in rare heritable conditions4. Interestingly, when
these mutated TRP channels are expressed in recombi-
nant systems, they generally display enhanced activity,
which suggests that blockade of these channels may pro-
vide therapeutic benefit.
To date, target validation of TRP channels has largely
been generated via genetic studies; by comparison, the
identification of chemical modulators of TRP channels
is in its infancy. Several natural ligands (for example,
capsaicin and menthol) have provided valuable insights
into the pharmacology of TRP channels (reviewed in
REFS 1,2,5). Although these molecules can be informa-
tive when they are used as tools for compound screen-
ing, they rarely display the potency, selectivity and/or
the physical properties that are desirable in modern
drug discovery programmes. However, despite these
obstacles several pharmaceutical companies have been
able to develop blockers of TRP cation channel subfam-
ily V, member 1 (TRPV1; also known as the capsaicin

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REVIEWS

Pruritus
Pruritus (also called an itch) is
an unpleasant cutaneous
sensation that is associated
with an urge to scratch. Various
categories of pruritus have
been suggested, including
pruriceptive itch (which arises
from skin conditions),
neurogenic itch (which is
caused by systemic disorders),
neuropathic itch (which is due
to a primary neurological
disorder) and psychogenic itch.
receptor); these blockers have been sufficiently safe and
effective in preclinical studies to merit their testing in
clinical trials. Many of these trials are still underway
(TABLE 1; Supplementary information S1 (box)), but the
results of published trials have not been straightforward;
rather, they have raised new questions regarding the role
of TRPV1 in humans.
Despite these setbacks, we believe that the pace of
drug discovery in the field of TRP channels has inten-
sified. The diversity in the expression, function and
structure of TRP channels provides the opportunity
to generate novel, selective chemical entities that can
be tested in diverse clinical indications. Molecules that
target TRPV3 have entered Phase I trials6 (see the Sanofi
website), and blockers of TRP cation channel subfamily
A, member 1 (TRPA1)6, TRP cation channel subfamily
M, member 8 (TRPM8)7 and TRPV4 (REF. 8) have been
efficacious in preclinical disease models and devoid of
unexpected acute adverse effects that could limit their
tolerability (TABLE 2).
Although results from clinical trials will serve as the
final arbiters of the utility of TRP channel modulators
as therapeutics, current evidence indicates that these
channels contribute to the development and/or progres-
sion of the symptoms of many diseases (for example,
neuropathic pain, overactive bladder, asthma, anxiety
disorders and pruritus) and that they are therapeutic
targets that are amenable to blockade by small mole-
cules. In this Review, we summarize the state-of-the-art
developments in this rapidly evolving field, highlight
crucial advances and look ahead to the next steps in
elucidating the roles of TRP channels in neurology, der-
matology, pulmonology, cardiology, urology, oncology
and heritable diseases.
TRP channels as analgesic targets
The role of TRP channels is best understood in the pain
area (FIG. 2). TRPV1 and TRPV3 antagonists have already
advanced to clinical trials (TABLE 1), whereas TRPA1
antagonists (TABLE 2) are still in preclinical development.
TRPV1. As the desensitization of nociceptive neurons to
capsaicin has analgesic potential5, the cloning of the cap-
saicin receptor, TRPV1 (REF. 9), has spurred considerable
efforts in the pharmaceutical community to find TRPV1
antagonists. However, side effects associated with the use
of TRPV1 antagonists have so far prevented any com-
pounds from progressing beyond testing in Phase II tri-
als. Particular concerns have surfaced around the effects
of TRPV1 antagonism on the regulation of body tem-
perature10 and in the detection of noxious heat (S. Eid,
personal communication).
TRPV1 and regulation of body temperature.
Trpv1‑null9,11 and -knockdown12 mice have an appar-
ently normal body temperature, despite the fact that they
prefer lower ambient temperatures13. These characteris-
tics are also observed in rats in which TRPV1‑expressing

Box 1 | Introduction to TRP channels

The transient receptor potential (TRP) cation channel superfamily is a diverse family of 28 cation channels that have varied
physiological functions, including thermal sensation, chemosenation, magnesium transport and iron transport (reviewed in
REF. 3). The TRP channel superfamily is classified into six related subfamilies: TRP cation channel subfamily C (canonical;
TRPC), TRP cation channel subfamily V (vanilloid; TRPV), TRP cation channel subfamily M (melastatin; TRPM), TRP cation
channel subfamily A (ankyrin; TRPA), TRP cation channel polycystin subfamily (TRPP) and TRP cation channel mucolipin
subfamily (TRPML)3.
The TRPML and TRPP subfamilies were named after the human diseases they are associated with (mucolipidosis and
polycystic kidney disease, respectively). The founding member of the TRPM subfamily, TRPM1, was identified via
comparative analysis of genes that distinguish benign nevi from malignant melanoma146. The TRPA subfamily has only one
known member (TRPA1) and its name refers to the unusually high number of ankyrin repeats at the amino terminus of the
channel protein (FIG. 1). Mammalian TRP channels that are most similar to the product of the Drosophila melanogaster Trp
gene are referred to as TRPC proteins3. The TRPV subfamily was identified following expression cloning of TRPV1, which is
the receptor for the prototypical irritant vanilloid, capsaicin9.
Overall, few generalizations can be made about TRP channels. Most members of the TRP channel superfamily share a low
level of structural similarity (FIG. 1), but some channels — such as TRPC3 and TRPC7, as well as TRPV5 and TRPV6 — are
highly homologous to each other3. Most of the channels are predicted to have six transmembrane domains and large
intracellular amino and carboxyl termini (FIG. 1). Many TRP channels form functional channels as homotetramers, although
heteromultimerization is not uncommon3. The latter phenomenon may have important implications in drug discovery as it
is crucial for understanding the endogenous subunit composition of the channels so that TRP channels can be
appropriately targeted with a pharmacological agent.
Consistent with their diverse structure, TRP channels also serve diverse functions. Although most members of the TRP
channel superfamily are cation channels with limited selectivity for calcium, both calcium‑selective (such as TRPV5 and
TRPV6) and sodium-selective (such as TRPM4 and TRPM5) members of the TRP channel subfamilies exist3. In addition, some
TRP channels transport non-canonical cations such as iron (TRPML1) or magnesium (TRPV6). Temperature also exerts
profound effects on several TRP channels. Although TRPV1 and TRPM8 have been clearly demonstrated to serve as sensors
for changes in environmental temperature, many other TRP channels have temperature coefficients such that a change in
temperature of 10°C has profound effects on channel activity3. These include TRPV2, TRPV3, TRPV4, TRPM2, TRPM4,
TRPM5 and TRPA1.
Data from animal models and human genetic studies have shown that TRP channel dysfunction (which is known as TRP
channelopathy) can cause various pathological conditions, including an inherited pain syndrome, multiple kidney diseases
and skeletal disorders (reviewed in REF. 4).

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Figure 1 | Diversity in structure among TRP channel families. The six transient receptor potential (TRP) cation families
0CVWTG4GXKGYU^&TWI&KUEQXGT[
contain very different motifs in their amino and carboxyl termini. The TRP cation channel subfamily V (TRPV), TRP cation
channel subfamily A (TRPA) and TRP cation channel subfamily C (TRPC) families have amino terminal ankyrin repeat (AnkR)
domains that are not present in other TRP channel subfamilies. The TRP box, which is found in the TRPV, TRP cation channel
subfamily M (TRPM) and TRPC families, is thought to be involved in gating. TRP cation channel polycystin subfamily (TRPP)
and TRP cation channel mucolipin subfamily (TRPML) proteins both have endoplasmic reticulum (ER) retention domains that
may be due to their functional localization on intracellular organelles. aa, amino acids; CIRB, calmodulin/inositol-1,4,5-tris-
phosphate (Ins(1,4,5)P3) receptor binding domain; NUDIX, nucleoside diphosphate-linked moiety X; PDZ, acronym for
postsynaptic density protein 95 (PSD95), Drosophila disc large tumour suppressor (DLGA) and zonula occludens protein 1
(ZO1). Image is reproduced, with permission, from REF. 180 © (2003) Macmillan Publishers Ltd. All rights reserved.

neurons have been ablated by high-dose capsaicin
treatment, which was administered when the rats were
neonates5. Therefore, the discovery that some TRPV1
antagonists cause hyperthermia in preclinical studies
and humans was somewhat unexpected10.
Is the hyperthermic action of TRPV1 antagonists
separable from their analgesic action? Several studies
have noted that treatment with antagonists that block
the three primary TRPV1 activators (that is, capsaicin,
low pH and heat) in vitro results in transient hyper-
thermia in experimental animal models (reviewed in
REF. 14). The severity of this effect varies depending on
the compound used but it is attenuated after several days
of dosing 15. In human volunteers, AMG517 (TABLE 1)
caused a hyperthermic response that lasted for 1–4 days
and raised body temperatures up to 40.2°C10. Other clin-
ical studies have also shown that TRPV1 antagonists
(for example, ABT‑102 (REF. 16) and AZD1386 (REF. 17);
TABLE 1) are associated with hyperthermia, although the
effects of these antagonists were not as pronounced as
the effects that were observed with AMG517.
In rats, it was possible to eliminate hyperthermia
while preserving analgesic activity by differential block-
ade of TRPV1 activation. Compounds (for example,
AMG8562; see Supplementary information S2 (table))
that prevented the activation of rat TRPV1 by capsai-
cin, but not by low pH or heat, had no effect on body
temperatures in the rat models; however, these com-
pounds still caused hyperthermia in dogs18. How well
this translates into clinical studies remains to be seen.
Notably, PHE377 (which is currently in Phase Ib trials)
did not cause hyperthermia in rats or dogs, although it
did inhibit all three major modalities of TRPV1 activa-
tion (see the PharmEste website).

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Table 1 | Therapeutic targeting of TRPV1

Compound Therapeutic indications Stage of development (status) Published data and press releases
Agonists*
ALGRX‑4975 Analgesia after total knee replacement Phase III trial (ongoing) See the Drugs.com website for further information
surgery and bunionectomy on Anasevia’s Phase III trial results
WN‑1001 Cluster headache, osteoarthritis Phase III trial (completed) ClinicalTrials.gov identifier: NCT00033839
NGX‑4010 (Qutenza; Postherpetic neuralgia Phase III trial (ongoing) See Drugs.com website for further information on
Astellas Pharma/ post-hepatic FDA approval of Qutenza
NeurogesX)
Antagonists‡
ABT‑102 Pain associated with inflammation, Phase I trial ClinicalTrials.gov identifier: NCT00854659
tissue injury and ischaemia
AMG‑517 Pain Phase Ib trial (terminated) REFS 11,21
AZD‑1386 Chronic nociceptive pain and GERD Phase II trial (terminated) REF. 19
DWP‑05195 Neuropathic pain Phase I trial (ongoing) Press release: 21 January 2009 (Daewoong
Pharmaceutical website)
GRC‑6211 Pain, migraine, urinary incontinence- Phase II osteoarthritis trial Press release: 24 October 2008 (Glenmark
associated pain and osteoarthritis (suspended) Pharmaceuticals website)
JTS‑653 Pain Phase II trial (ongoing) Clinical Development of Pharmaceuticals; 29 July
2010: Japan Tobacco website
MK‑2295 Pain Phase II trial (completed) ClinicalTrials.gov identifier: NCT00387140
PHE377 Neuropathic pain Phase I trial (ongoing) See the PharmEste website for further information
SB‑705498 Pain, migraine and rectal pain Phase II migraine and rectal ClinicalTrials.gov identifiers: NCT00269022;
pain trial (terminated) NCT00731250
Phase II non-allergic intranasal
rhinitis trial (ongoing)
GERD, gastroesophageal reflux disease; TRPV1, transient receptor potential cation channel subfamily V, member 1. *These agonists have been reviewed in REF. 20.
‡
See Supplementary information S1 (box) for further information.

TRPV1 antagonists and noxious heat perception in
humans. Clinical studies have confirmed the role of
TRPV1 as a noxious heat sensor in humans (S. Eid,
personal communication). Indeed, the threshold for
detecting painful heat was considerably elevated in
non-sensitized skin of healthy volunteers following
oral administration of 400 mg of SB‑705498 per day
(Supplementary information S2 (table)), with sub-
sequent studies reporting blunted heat perception in
healthy human subjects, which was not desensitized
after repeated dosing 19. This effect could potentially
cause scalding injuries during common activities such
as taking a hot shower or consuming hot food or bever-
ages. Indeed, some subjects taking MK‑2295 perceived
potentially harmful temperatures as innocuous (S. Eid,
personal communication). In randomized clinical trials,
similar findings were reported using ABT‑102 (which
was administered at a dose of up to 4 mg twice a day) and
AZD1386 (which was administered at a single daily dose
of 95 mg)16,17. Notably, there were no other relevant safety
findings in these two trials and the investigators felt that
AZD1386 may have clinical potential in relieving pain
associated with gastroesophageal reflux disease17.
TRPV1 agonists (capsaicin and resiniferatoxin) in the
clinic. Topical TRPV1 agonists (for example, capsaicin
creams) have been used clinically for many years to alle-
viate chronic painful conditions such as diabetic neurop-
athy 20. An occlusive high-concentration capsaicin patch
(Qutenza; NeurogesX) (TABLE 1) was recently approved
for the treatment of various pain conditions21. Injections
of resiniferatoxin, an ultrapotent capsaicin analogue5
(see Supplementary information S2 (table)), are being
evaluated as a so-called ‘molecular scalpel’ to achieve
long-term analgesia in patients with cancer who have
chronic, intractable pain (ClinicalTrials.gov identifier:
NCT00854659). A novel approach for minimizing the
burning pain reaction at the application site, which is the
main adverse effect of capsaicin administration, is the
activity-dependent targeting of TRPV1 using perma-
nently charged agonists that only permeate the core of
the TRPV1 channel when it is open22. Such agonists are
expected to target (and subsequently desensitize) hyper-
active TRPV1 and spare normal nociception.
TRPA1. TRPA1 is a receptor for a range of environmental
irritants and oxidants23–29, and it has an important role in
many preclinical models of pain6. TRPA1 is directly acti-
vated by structurally diverse chemicals. These include:
cinnamaldehyde (which is present in cinnamon), allyl
isothiocyanate (which is found in mustard oil), allicin
(which is present in raw garlic), formalin (a chemical
that is commonly used to induce experimental pain and
is also a hazardous respiratory irritant) and icilin, which
is a synthetic compound that produces a sensation of
extreme cold (Supplementary information S2 (table);
reviewed in REF. 6). When they are applied topically,
many of these compounds cause pain in humans. Several

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Table 2 | Stage of development of drugs targeting TRP channels

Channel Findings from in vitro Genetic deletion Studies linking Published Efficacy with Published clinical
studies studies mutation to pharmacological pharmacological trial data
disease modulators agents in vivo
TRPV1 Acts as a capsaicin Decreased sensitivity None reported Discussed in Table 1 Desensitization See Supplementary
receptor, and is to noxious heat, and to agonists; information S1
a heat-activated reduced thermal pharmacological (box)
non-selective cation hyperalgesia in blockade by
channel2 numerous pain models2 antagonists1,2,5
TRPV3 A heat-activated Effects on skin, heat None reported Agonists: incensole CCI, CFA GRC 15300 (details
non-selective sensation44,50 acetate, 2‑APB (GRC 15300)49 not reported)6
cation channel that (nonspecific49) See the Sanofi
is potentiated by Antagonists: website for further
repeated activation6,49 GRC 15300 (no information
structure available)
TRPV4 A non-selective Increased bone Skeletal dysplasias Agonists: 4aPDD, Agonists cause None
cation channel. Acts density114,115 altered including SMDK, GSK1016790A profound
as an osmosensor urination brachyolmia type (REF. 69) circulatory
that is activated by 3, hereditary Antagonist: collapse110 and
metabolites of the motor and sensory HC‑067047 (REF. 67) antagonists
arachidonic acid neuropathy have efficacy in
pathway. Involved type 2C, bladder cystitis
in osteoclast scapuloperoneal (HC‑067047;
differentiation and and congenital REF. 67)
bone resorption114,115 distal SMA116–120
TRPC3 A diacylglycerol- Ataxia and reduced None reported Antagonist: Reduced cardiac None
activated non-selective mGluR signalling140 ethyl‑1-(4‑2,3,3- hypertrophy in
cation channel that is trichloroacrylamide) mice
a downstream target phenyl)‑5-
of multiple Gq-coupled (trifluoromethyl)-
GPCRs3 1H-pyrazole‑4-
carboxylate165
TRPC5 A non-selective Reduced anxiety None reported None None None
cation channel that is behaviours
potentiated by calcium and reduced
and Gq-coupled CCK4-invoked
GPCR signalling, and currents in
forms heteromultimers hippocampal slices141
with TRPC13
TRPML1 An intracellular Deletion in Drosophila Mucolipidosis None None None
iron-permeable melanogaster results in type IV3,4
channel131 neurodegeneration*166
TRPM1 Cloned following a Mutation identified as Associated with None None None
screen for genes that the potential cause of the complete
mark melanoma cells146; heritable stationary form of human
is a marker for melanoma night blindness in congenital
progression146; small horses168 stationary night
current, activated by blindness169–171
steroids and blocked by
zinc167
TRPM2 An oxidant sensor Increased blood Downregulation Antagonist: None None
that is potentiated by glucose levels in or mutation may N‑(p-amylcinnamoyl)
increases in levels of Trpm2–/– mice172 be associated with anthranilic acid173
intracellular calcium, bipolar disorder
cyclic ADP ribose, or hereditary
hydrogen peroxide and deafness144
NADP172
TRPM6 An outwardly rectifying Genetic deletion is Inherited None None None
channel, involved in lethal174; heterozygotes hypomagnesaemia4
magnesium transport4 show mild
hypomagnesaemia174
TRPM7 An outwardly rectifying Knockout is lethal; Potential Antagonists: NDGA, None None
channel. siRNAs targeted deletion susceptibility locus AA861 and MK886;
reduce cell death in in T cells disrupts for Guamanian Antagonists:
hippocampal neurons thymopoiesis without amyotrophic nafamostat mesylate‡
owing to oxygen and affecting magnesium lateral sclerosis activates TRPM7
glucose deprivation145 homeostasis175 and parkinsonism under physiological
dementia176 conditions177

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Table 2 cont. | Stage of development of drugs targeting TRP channels

Channel Findings from in vitro Genetic deletion Studies linking Published Efficacy with Published clinical
studies studies mutation to pharmacological pharmacological trial data
disease modulators agents in vivo
TRPM8 A cold- and Affects the sensation None reported Agonists: menthol, Agonists: wet dog Agonists: cutaneous
menthol-activated of environmental icilin, WS‑12 and shakes; analgesia menthol (migraine);
non-selective cation cold; mild pain WS‑5 (REF. 1) in CCI model of menthol patch
channel (reviewed in phenotype52–54 Antagonists: chronic pain55 (mild to moderate
REFS 1,2) benzimidazoles, Antagonists: muscle strain)78
AMTB (REF. 70) AMTB decreased Antagonists: D‑3263
volume-induced (ClinicalTrials.
voiding events70 gov identifier:
NCT00839631)
TRPP2 A non-selective cation Pkd2–/– mice usually Mutation in None None None
channel that forms die mid-gestation as a gene encoding
heteromultimers with result of kidney cysts, polycystic kidney
several other TRP oedema and placental disease 2 protein122
channels. Involved in abnormalities179
ciliary movement121,123
TRPA1 Channel activated by Reduced sensitivity Mutations cause Agonists: multiple Formalin, AITC, None reported
reactive chemicals, to environmental familial episodic reactive chemicals cinnamaldehyde-
potentiated by cold irritants; reduced pain syndrome43 (endogenous and flinch33–35;
pain behaviours in exogenous) that CFA-cold38,
numerous models; lead to sulfhydryl mechanical35;
reduced responses modification of SNL-mechanical;
in an allergic asthma cysteine reidues SNI-cold;
model Antagonists: MIA-induced OA40
HC‑030031
(REF. 33), AP‑18
(REF. 34), A‑967079
(REFS 40,41)
2-APB, 2‑aminoethoxydiphenyl borate; 4aPDD, a-phorbol 12,13-didecanoate; AITC, allyl isothiocyanate; AMTB, N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-
N-(2-thienylmethyl)benzamide hydrochloride; CCI, chronic constriction injury; CCK4, cholecystokinin 4; CFA, complete Freund’s adjuvant; DAG, diacylglycerol;
GPCR, G protein-coupled receptor; IC50, half-maximal inhibitory concentration; mGluR, metabotropic glutamate receptor; MIA, monoiodoacetate; OA,
osteoarthritis; SMA, spinal muscular atrophy; SMDK, spondylometaphyseal dysplasia, Koslowski type; SNI, spared nerve injury; SNL, spinal nerve ligation; TRPA1,
transient receptor potential cation channel subfamily A, member 1; TRPC1, TRP cation channel subfamily C, member 1; TRPM1, TRP cation channel subfamily M,
member 1; TRPML1, TRP cation channel mucolipin subfamily 1; TRPP2, TRP cation channel polycystin subfamily 2 (also known as PKD2); TRPV1, TRP cation channel
subfamily V, member 1. *This is possibly owing to reduced clearance of macromolecules and apoptotic cells. ‡IC50 varies with concentration of divalent cations.

endogenous compounds (for example, 4‑hydroxy-
nonenal, A‑ and J‑series prostaglandins and hydrogen
peroxide) that are released following tissue damage and
inflammation also directly activate TRPA1 via covalent
binding and induce pain behaviours in mice25,30,31.
Key pronociceptive signalling pathways also indi-
rectly potentiate TRPA1 activity by increasing intracel-
lular calcium concentration. For example, bradykinin,
proteinase-activated receptor 2 and nerve growth factor
potentiate TRPA1 currents via their respective receptors
(reviewed in REFS 1,6). Furthermore, mice with disrupted
TRPA1 function fail to develop pain behaviour and ther-
mal and mechanical hypersensitivity after intraplantar
injection of bradykinin24,32, which provides evidence that
this phenomenon is relevant in vivo.
Collectively, the above results led to efforts that aimed
to identify TRPA1 antagonists as therapies for treating
pain6. Two moderately potent but highly selective TRPA1
antagonists, HC‑030031 (REF. 33) and AP‑18 (REF. 34),
have subsequently been discovered (see Supplementary
information S2 (table)).
In rodents, HC‑030031 reduces acute and chronic
inflammatory pain, and reduces neuropathic pain with-
out having any apparent effect on motor coordination
or noxious cold detection33,35. A structurally related
compound, Chembridge‑5861528 (Supplementary
information S2 (table)), prevents the development of
mechanical hyperalgesia in animal models of diabetes-
induced pain, which suggests that endogenously pro-
duced oxidant and inflammatory mediators may act via
TRPA1 to contribute to diabetes-induced pain36. In addi-
tion, animals that were treated with Chembridge‑5861528
had reduced nerve damage in response to streptozotocin,
which indicates that TRPA1 antagonists could be used for
disease modification in painful diabetic neuropathy36. In
rats, intrathecal TRPA1‑targeted antisense oligonucleo-
tides37 or TRPA1 antagonists can also dramatically reduce
cold hypersensitivity after nerve injury or inflammation35.
Cold temperatures are a considerably weaker activa-
tor of the TRPA1 channel38. However, cold temperatures
dramatically potentiate TRPA1 activity in the presence of
other agonists38. Furthermore, the selective TRPA1 antag-
onist HC‑030031 reduces cold hypersensitivity in rodent
models of inflammatory and neuropathic pain without
altering normal cold sensation in naive animals33,38,39.
Similarly, A‑967079 — a compound that is structurally
similar to AP‑18 (Supplementary information S2 (table))
— reduces cold hypersensitivity after nerve injury without
affecting acute responses to environmental cold40. Thus,
TRPA1 appears to selectively mediate cold hypersensitiv-
ity in pathological conditions in which other activators of
the channel are also present.

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© 2011 Macmillan Publishers Limited. All rights reserved

 REVIEWS

6428 2CKPCXQKFCPEG
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Figure 2 | TRP channels as nociceptors. Sensory neurons express multiple transient receptor potential (TRP) channels. TRP
0CVWTG4GXKGYU^&TWI&KUEQXGT[
cation channel subfamily V, member 1 (TRPV1), TRPV3 and TRPV4 all respond to warming temperatures. Noxious heat
activates TRPV2, but the physiological relevance of this is unclear. Acids are robust activators of TRPV1 and bases have
emerged as activators of TRP cation channel subfamily A, member 1 (TRPA1). TRPA1 is a key chemoreceptor that responds
to scores of reactive chemicals. At higher concentrations, some of these chemicals also activate TRPV1. TRP cation channel
subfamily M, member 8 (TRPM8) serves as the key receptor for environmental cold, although TRPA1 also has a role in cold
hyperalgesia. Activation of any of these TRP cation channels can trigger action potentials in the sensory neuron. Some of
these channels, such as TRPV1, are also expressed in the spinal cord, where they seem to have an important role in the
central nervous system as well. DRG, dorsal root ganglion. Image is reproduced, with permission, from REF. 181 © (2002)
Macmillan Publishers Ltd. All rights reserved.

Although TRPA1 may have an analogous role in
nociceptor mechanotransduction, whether TRPA1 is
mechanically activated per se remains to be determined.
In rats, A‑967079 reduced the frequency of firing of wide-
range dynamic neurons in lamina V of the spinal cord in
response to noxious mechanical stimuli41. These data are
consistent with data taken from an isolated rat skin-nerve
preparation using HC‑030031 and from mice lacking
TRPA1, which suggests that TRPA1 is required for pro-
longed neuronal firing in response to certain high-inten-
sity mechanical stimuli42.
In conclusion, preclinical data (and data from a
recent human genetic study 43) highlight TRPA1 antago-
nists as a promising new approach for the treatment of
acute and chronic pain. The current status of several
drug development programmes is presented in TABLE 2.
TRPV3. Changes in the levels of expression of TRPV3,
which is usually highly expressed in the skin44,45, can occur
in human disease states. For example, TRPV3 expres-
sion is increased in painful breast tissue46 and decreased
in basal keratinocytes that are recovered from patients
with diabetic neuropathy 47. TRPV3 appears to be unique
among TRP channels in that repeated stimulation of the
channel leads to sensitization that depends on the pres-
ence of calcium48. Activation of Gq-coupled GPCRs —
including the histamine and bradykinin receptors — also
potentiates TRPV3 activity 45, thus allowing TRPV3 to
serve as a convergence point for multiple pain pathways
(reviewed in REF. 49). TRPV3 is activated in response to
temperatures in the range of 31–39 °C and to the chemicals
camphor and 2‑aminoethoxydiphenyl borate (reviewed in
REFS 1,49). Trpv3‑null mice had defects in thermal selec-
tion behaviour in response to innocuous heat, and defects
in withdrawal behaviour in response to noxious heat 50.
Taken together, these findings suggest an important role
for TRPV3 in pain transduction. TRPV3 antagonists have
shown efficacy in preclinical neuropathic and inflamma-
tory pain models (TABLE 2), and one molecule has entered
Phase I clinical trials (see the Sanofi website).
TRPM8. In sensory ganglia, TRPM8 expression dis-
tinguishes a specific subpopulation of primary sensory
neurons that are cold-sensitive (reviewed in REFS 1,2).

NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 | 607

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REVIEWS

The finding that the heat-sensitive TRPV1 and the cold-
sensitive TRPM8 are co-expressed in some neurons51
underlines the hypothesis that individual neurons may
be able to sense ranges of both hot and cold temperatures.
In vitro, TRPM8 is activated by cool temperatures in
the range of 10–23 °C, as well as the cooling agents men-
thol (Supplementary information S2 (table)) and icilin
(reviewed in REFS 1,2). Furthermore, TRPM8‑deficient
mice showed no preference for warm temperatures over
cool temperatures, and they exhibited impaired cold
avoidance behaviour, which highlights the essential role
of TRPM8 in the sensation of environmental cold52–54.
Controversy surrounds the utility of TRPM8 as an
analgesic target. The TRPM8 agonist menthol decreases
nociceptive responses in animal models of inflammatory
and neuropathic pain55. However, TRPM8 antagonism
may also provide relief from some forms of pain. For
example, Trpm8–/– mice failed to develop cold allodynia
after chronic constriction injury or injection of complete
Freund’s adjuvant (CFA)54. Importantly, a TRPM8 antag-
onist reduced cold allodynia in a chronic constriction
injury model of chronic neuropathic pain, thus recapitu-
lating the phenotype of genetic deletion56.
The observation that both TRPM8 agonists and
TRPM8 antagonists may be useful for the treatment of
pain highlights the importance of selecting appropriate
models to examine TRP channel modulators.
TRP channels in bladder disorders
Several TRP channels are expressed in the bladder —
in the urothelium, nerve endings and detrusor muscle
(FIG. 3) — where they are thought to function as sensors of

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Figure 3 | Roles of TRP channels in bladder functions. The micturition reflex is mediated by transient receptor
potential cation channel subfamily V, member 1 (TRPV1)-positive nerves and probably — albeit0CVWTG4GXKGYU^&TWI&KUEQXGT[
to a lesser degree — also
by TRP cation channel subfamily M, member 8 (TRPM8)-positive nerves. These same neurons convey nociceptive
information (for example, bladder pain that is secondary to cystitis) to the central nervous system. TRPV4 is a key player in
bladder function because it is present in both the urothelium and the detrusor muscle, and it is activated by stretch
(bladder distension) and hypo-osmolar urine. The activator of TRPM8 in the bladder remains to be determined. The
micturition reflex is under the control of a descending central nervous system pathway; when this pathway is disrupted
(for example, as a result of spinal cord injury or multiple sclerosis), it becomes autonomous and partly driven by TRPV1. The
existence of functional TRPV1 in urothelial cells remains controversial, as evidence for (REFS 64, 66) and against (REF. 65)
the presence of a funtional channel has been presented. Collectively, these findings imply a therapeutic potential of
TRPV1 antagonists (or TRPV1 desensitization) and/or TRPM8 agonists as therapies in painful bladder disorders (and in
pain induced by benign prostatic hyperplasia) and in an overactive bladder. These findings also suggest that TRPV4
blockers could be useful in the management of an overactive bladder. DRG, dorsal root ganglion.

608 | AUGUST 2011 | VOLUME 10 www.nature.com/reviews/drugdisc

© 2011 Macmillan Publishers Limited. All rights reserved


Prurigo nodularis
A skin condition that is
characterized by itchy nodules
(circumscribed, solid elevations
on the skin), which usually
appear on the arms or legs.
Pruritogens
Agents that induce itch by
stimulating pruritoceptive
sensory afferent neurons. In
the skin, they are synthesized
by and released from multiple
non-neuronal cell types and
include histamine, acids, ATP,
prostaglandins and
pro-inflammatory interleukins.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 | 609
stretch and chemical irritation (reviewed in REFS 57,58).
Intravesical administration of TRPV1 agonists has been
used in the management of the overactive bladder for
many years, largely on an empirical basis (reviewed in
REF. 58). The recent recognition of disease state-related
changes in the expression of TRP channels has provided
a new impetus to investigate the roles of these channels
in normal bladder function and dysfunction.
TRPV1. There is a dense network of nerve fibres that
express TRPV1 in the suburothelium and muscular
layer of the human renal pelvis, ureter, bladder and
urethra57,58, but the existence of functional TRPV1 in
the urothelium and detrusor smooth muscle remains
controversial59. The involvement of neuronal TRPV1 in
the micturition reflex is well established57,58. Indeed, rats
in which TRPV1‑expressing nerves have been ablated
by neonatal capsaicin treatment develop a dis-
tended bladder 5. Trpv1–/– mice, however, show only
spotty incontinence 60. It is possible that another
protein compensates for the lack of TRPV1 or that
TRPV1‑containing, neuron-specific gene products
other than TRPV1 contribute to the phenotype that is
observed in these animals.
In humans, desensitization therapy using intravesical
TRPV1 agonists (capsaicin or resiniferatoxin) is based
on the concept that the C fibre-driven micturition reflex
— which is inactive in adult life — reassumes control
of micturition in the overactive bladder, in both neu-
rogenic and non-neurogenic cases57,58. In patients with
neurogenic detrusor overactivity disorders, intravesical
administration of resiniferatoxin provides symptomatic
relief by increasing bladder capacity and decreasing the
frequency of daily episodes of incontinence61. Moreover,
intrathecal administration of resiniferatoxin blocks
detrusor overactivity in rats that have complete spinal
cord transection62, and intravesical administration of
resiniferatoxin reduces the frequency of incontinence
episodes in patients with spinal cord injury (reviewed
in REFS 61,63).
The therapeutic value of TRPV1 antagonists in manag-
ing detrusor muscle overactivity is unclear, as no endoge-
nous agonist has been identified in the bladder of patients
who suffer from incontinence. By contrast, the pain and
bladder hyperactivity that accompany interstitial cystitis
are thought to be amenable to therapy with TRPV1 antag-
onists63. In a feline model of interstitial cystitis, abnor-
mally enhanced responses to capsaicin were detected
after TRPV1 phosphorylation by protein kinase C64.
In mice, genetic manipulation of the Trpv1 gene prevents
bladder reflex hyperactivity and spinal FOS overexpres-
sion in experimental models of cystitis60. The TRPV1
antagonist GRC‑6211 (Supplementary information S2
(table)) ameliorates micturition reflex activity in the
chronically inflamed bladder 65. Collectively, these find-
ings imply a therapeutic value for TRPV1 antagonists in
the symptomatic treatment of interstitial cystitis.
TRPV4. In the bladder, TRPV4 is predominantly
expressed in the urothelium, but it is also present in
the detrusor muscle57,59. Trpv4–/– mice show an altered
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
micturition pattern that is characterized by increased
intermicturation intervals and spotting behaviour due
to spontaneous (that is, not reflex-driven) contractions
of the detrusor muscle66. In addition, Trpv4–/– mice show
reduced urinary frequency and increased void volume
after bladder damage caused by intravesical administra-
tion of cyclophosphamide67. Based on these findings, it
has been postulated that TRPV4 plays a crucial part in
the mechanosensory pathway in the bladder by detect-
ing changes in intravesical pressure. Indeed, mechani-
cal stretch has been shown to activate urothelial TRPV4
in vitro68.
Activation of TRPV4 that is located in the detrusor
muscle can lead to muscle contractions. Accordingly,
the TRPV4 agonist GSK1016790A (Supplementary
information S2 (table)) causes direct contraction of
the bladder, even in the absence of the urothelium69.
As predicted by data generated from Trpv4–/– mice, the
TRPV4 antagonist HC‑067047 (Supplementary infor-
mation S2 (table)) improved bladder function in mice
with cyclophosphamide-induced cystitis67. Acute dosing
of HC‑067047 did not alter water intake, core body tem-
perature, thermal selection behaviour, heart rate, loco-
motion or motor coordination in vivo. Taken together,
these observations imply that TRPV4 antagonists could
be valuable in the management of an overactive bladder.
TRPM8. In the human bladder, TRPM8 is present in
both urothelial and suburothelial myelinated nerve
fibres, with increased expression in patients who have
bladder pain or idiopathic detrusor overactivity 70. The
TRPM8 agonist menthol evokes the micturition reflex
in humans70. Conversely, the TRPM8 antagonist AMTB
(Supplementary information S2 (table)) decreases the
frequency of volume-induced bladder contractions in a
rat model of painful bladder syndrome71. These findings
imply that TRPM8 antagonists have therapeutic potential
in the management of bladder disorders that are charac-
terized by pain and/or overactivity of the detrusor muscle.
TRP channels in the skin
Populations of non-neuronal cells within the skin express
many different types of TRP channels (FIG. 4), which are
thought to be involved in various key cutaneous func-
tions including skin-derived pruritus, proliferation, dif-
ferentiation, cancer and inflammatory processes (BOX 2).
TRPV1 as a key molecule in itch. TRPV1 is involved
in the development of skin-derived pruritus, which is
thought to occur through itch-specific subpopulations of
TRPV1‑expressing sensory afferent neurons (also known
as pruritoceptive neurons; reviewed in REFS  72,73).
TRPV1 is also expressed in non-neuronal cell types of
human skin74, and its expression is elevated in epidermal
keratinocytes of patients with prurigo nodularis75.
Certain endogenous signalling molecules that poten-
tiate TRPV1 activity (including acids, ATP, lipoxyge-
nase products, prostaglandins and histamine) are also
potent pruritogens (reviewed in REFS 72,73). It is probable
that on sensory neurons, histamine indirectly activates
TRPV1 through histamine H1 receptor-dependent
REVIEWS
Alopecia
A type of pathological hair loss
that mostly affects the scalp.
The most common forms of
alopecia are alopecia
universalis, alopecia areata and
alopecia androgenetica.
Telogen Effluvium, which is
characterized by diffuse hair
shedding, is a form of alopecia.
Hirsutism
Excessive and increased hair
growth (especially in women)
on regions of the body where
the occurrence of hair normally
is minimal or absent.
Dermatitis
A universal term describing
inflammation of the skin. It can
be induced by various factors
such as allergens (allergic
dermatitis), infections, eczema
(atopic dermatitis) or external
compounds (contact
dermatitis).
Apnoea
Prolonged periods of time
without respiratory flow.
Although humans can perform
this manoeuvre voluntarily (by
holding their breath), reflex
apnoeas can be induced in
human volunteers and animals
by irritant stimulation of the
respiratory tract.
610 | AUGUST 2011 | VOLUME 10 www.nature.com/reviews/drugdisc
synthesis of 12‑hydroperoxyeicosatetraenoic acid,
which is an endogenous activator of TRPV1 (reviewed
in REF. 2). Consistent with this finding, genetic deletion
of Trpv1 in mice substantially suppressed histamine-
induced scratching behaviour 76. In humans, TRPV1
mediates histamine-induced experimental itch77, as well
as pruritus in patients with seasonal allergic rhinitis78. By
contrast, histamine-independent itch — caused by chlo-
roquine or the endogenous pruritogen peptide BAM8‑22
(originally isolated from bovine adrenal medulla) — is
predominantly mediated by TRPA1 (REF. 79).
Paradoxically, the loss of TRPV1‑expressing neu-
rons is also associated with excessive itch. Rats that
have had their capsaicin-sensitive neurons chemically
ablated may develop skin ulcers as a result of extensive
scratching 80. Mice lacking the vesicular glutamate trans-
porter 2 — thereby ostensibly disabling glutamatergic
neurotransmission in the spinal dorsal horn, which is
the termination site of TRPV1‑positive primary afferent
neurons — demonstrated enhanced scratching behav-
iour and reduced sensitivity to noxious heat 81,82. Clearly,
further neurophysiological studies in humans are
needed to dissect the multifaceted relationship between
TRPV1‑positive primary afferent neurons and pruritus.
Role of TRPV1 in the control of skin growth, skin cell
survival and cutaneous inflammation. It has been sug-
gested that TRPV1 participates in the regulation of
cutaneous growth and differentiation. TRPV1‑mediated
calcium influx in cultured human keratinocytes sup-
presses proliferation and promotes apoptosis 83,84. In
addition, activation of TRPV1 by either capsaicin or
heat alters the formation of the epidermal permeability
barrier in human skin in vivo85.
TRPV1 has also been suggested to regulate cutaneous
inflammation. Capsaicin-induced activation of TRPV1
on human epidermal and hair follicle-derived keratino-
cytes in vitro results in the release of several pro-inflam-
matory cytokines83. In addition, as ultraviolet irradiation
upregulates TRPV1 expression in human skin86, TRPV1
that is expressed on keratinocytes is a specific media-
tor of heat shock-induced and ultraviolet irradiation-
induced expression of matrix metalloproteinase 1
(REF. 87), an enzyme that is implicated in skin inflam-
mation and remodelling. Taken together, these findings
imply that topical TRPV1 modulators may be used in
the treatment of sunburn, acne vulgaris and alopecia or
hirsutism.
TRPV3. TRPV3, which is expressed at high levels by
keratinocytes88, is crucial in promoting epidermal bar-
rier formation and hair morphogenesis in mouse skin.
This probably occurs through the formation of a signal-
ling complex between TRPV3 and the epidermal growth
factor receptor44. Consistent with this concept, genetic
deletion of Trpv3 in mice caused hair abnormalities
(that is, wavy hair coat and curly whiskers)44,50, whereas
the constitutively active gain-of-function mutation
Trpv3Gly573Ser resulted in a spontaneous hairless pheno-
type in DS‑Nh mice (a mouse model of dermatitis)89,90.
As the activation of TRPV3 in organ cultures of human
© 2011 Macmillan Publishers Limited. All rights reserved
hair follicles also inhibited hair growth91, these findings
imply a therapeutic potential for topical TRPV3 agonists
and antagonists in the treatment of hirsutism and alo-
pecia, respectively.
TRPV3 is also involved in the development of skin
inflammation. Stimulation of TRPV3 in cultured
keratinocytes induced the release of pro-inflammatory
mediators45. Importantly, DS‑Nh mice develop skin
alterations that are similar to those seen in human atopic
dermatitis89. Moreover, Trpv3Gly573Ser transgenic mice that
express high levels of the mutated, constitutively active
TRPV3 protein in epidermal keratinocytes also sponta-
neously develop an inflammatory condition that is simi-
lar to human atopic dermatitis90. As the skin-targeted
Trpv3Gly573Ser transgenic mice also exhibit scratching
behaviour, these data suggest that TRPV3 channels may
function as important transducers of pro-inflammatory
signals in the pathogenesis of various forms of dermatitis.
TRP channels in the pulmonary system
The mammalian respiratory tract is lined with a dense
plexus of sensory fibres, including those that express
TRPA1 and TRPV1 (FIG. 5). Activation of this subset
of nerve fibres by irritant and/or inflammatory stimuli
triggers multiple reflexes — such as sneezing, cough-
ing, mucus secretion, bronchospasms and apnoea —
that limit ventilation and dilute and/or expel foreign
materials. Analogous to pain, in which inflammatory
mediators produce a hypersensitive response to vari-
ous stimuli, reflexes such as coughs are proposed to be
sensitized by mediators of inflammation and oxidant
stress, such that they become triggered by innocuous
stimuli. Thus, although a distinct and unusual subpopu-
lation of afferent fibres may be responsible for coughing
reflexes92, airway nociceptors appear to exert a consider-
able amount of control over the sensitivity of this reflex.
TRPV1. Capsaicin is a prototypical respiratory irritant
that causes noxious sensations as well as reflexes such
as coughing, sneezing and fluid secretion when it is
applied to the human respiratory mucosa (reviewed in
REF. 5). Increased sensitivity to capsaicin aerosols occurs
in several respiratory disorders of varying severity and
aetiology (reviewed in REF. 93). Alterations in capsaicin-
induced coughing may be due to enhanced TRPV1
expression or activity in airway sensory neurons, altera-
tions in the permeability of the epithelial barrier that
allows capsaicin to more readily access airway nocicep-
tor terminals and/or heightened responsiveness of the
central nervous system to afferent inputs. Intriguingly,
treatment with the non-selective cyclooxygenase inhibi-
tor indomethacin increases capsaicin-induced cough
thresholds in patients with asthma or chronic bronchitis
but not in healthy subjects94. These results offer com-
pelling evidence that inflammatory mediators that are
produced in diseased airways enhance the sensitivity of
airway reflexes in a manner that can be at least partially
reversed by pharmacological intervention.
Therapy using intranasal capsaicin to desensitize
TRPV1‑containing sensory neurons provides symp-
tomatic relief in patients with rhinitis95; however, this
 REVIEWS

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Hair cycle
A life-long regeneration
programme of the hair follicles
that can be divided into three
phases: anagen (growth),
catagen (apoptosis-driven
regression or involution) and
telogen (resting or quiescence,
preparation for the next anagen
phase). This cycle is controlled
by promoters (for example,
insulin-like growth factor 1 and
hepatocyte growth factor) and
inhibitors (for example,
interleukin‑1β, and
transforming growth factor‑β2)
Figure 4 | TRP channels in human skin. The role of transient receptor potential (TRP) channels in the skin is supported
0CVWTG4GXKGYU^&TWI&KUEQXGT[
by strong evidence (shown using continuous arrows) indicating that TRP cation channel subfamily V, member 1 (TRPV1) is
expressed by various cell types (sebocytes, keratinocytes, sensory neurons and cells of the hair follicles). TRPV1 activation
is shown to induce heat sensation and the development of skin-derived pruritus, and suppress sebaceous lipid synthesis.
Activation of TRPV1 and TRPV3 shifts the proliferation–differentiation balance of epidermal keratinocytes towards
differentiation and, along with TRPV4 and TRPV6, TRPV1 and TRPV3 are involved in the regulation of epidermal barrier
formation. Moreover, activation of TRPV1 and TRPV3 either on epidermal or hair follicle-derived keratinocytes results
in increased pro-inflammatory cytokine release, which suggests that these channels are key players in the in situ
immunoregulation of human skin. In addition, the hair cycle is regulated both directly (via stimulation of TRPV1 and
TRPV3) and indirectly (via TRPV1 activation that results in follicular growth factor production) by TRP channels.
Preliminary findings (indicated using dashed arrows) suggest that TRP cation channel subfamily C, member 1 (TRPC1)
and TRPC4 are likely to have antitumour effects, whereas TRP cation channel subfamily M, member 7 (TRPM7) regulates
melanogenesis of melanocytes. In addition, TRP cation channel subfamily A, member 1 (TRPA1) and TRPM8 may have a
synergistic effect with other TRP channels in the regulation of epidermal barrier formation and maturation (that is,
differentiation) of keratinocytes.

NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 | 611

© 2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
Respiratory irritation
A stereotypical reflex reduction
in respiratory rate exhibited by
small laboratory animals
following irritant aerosol
provocation. This behaviour
generally predicts the irritation
threshold for molecules in
humans.
Pilosebaceous unit
Consists of the hair shaft, the
hair follicle, the sebaceous
gland and the erector pili
muscle; causes the hair to
stand up when it contracts.
Sebum
A lipid-enriched, oily exocrine
product of the sebaceous
glands that has various
functions including waterproof
barrier formation, antimicrobial
activity, transport and
thermoregulation.
Basal cell carcinoma
The most common type of
malignant skin tumour, which
develops from the basal cell
layer of the epidermis. It rarely
metastasizes, but without
treatment it may cause
substantial destruction by
invading the deeper skin tissues.
Darier’s disease
A congenital skin condition
that is characterized by
dyskeratosis (abnormal
keratinization of the epidermis)
and the appearance of pruritic,
greasy and scaly skin papules
(circumscribed, solid elevations
on the skin) and plaques
(confluences of papules).
Vitiligo
A skin disorder that is
characterized by
depigmentation of patches of
skin. It develops as a result of
impaired functions or death of
skin melanocytes, which can be
induced by various factors,
such as autoimmune
conditions, genetic factors,
oxidative stress and infections.
Penh (enhanced pause)
A derived value that is
supposed to characterize the
ventilatory activity of freely
moving rodents in
plethysmography chambers
where airflow is measured.
Interpretation of this
measurement is debated
within the respiratory field.
612 | AUGUST 2011 | VOLUME 10 www.nature.com/reviews/drugdisc
Box 2 | Emerging functions of TRP channels in cutaneous biology
In the human pilosebaceous unit, capsaicin-induced activation of transient receptor potential cation channel subfamily V,
member 1 (TRPV1) suppresses hair shaft elongation and induces apoptosis-driven catagen regression84. In this study, TRPV1
activation was accompanied by a considerable alteration in the gene-expression profiles of the cells and modulation of
intrafollicular production of cytokines and growth factors that control human hair growth in vivo84. Interestingly, compared
to wild-type mice Trpv1 gene-deficient mice exhibited a significant delay in hair follicle cycling — that is, a delay in the
onset of the catagen phase158. This supports the concept that TRPV1 may exert functions that are primarily
growth-inhibitory in mammalian skin epithelium. Moreover, stimulation of TRPV1 expressed in human sebaceous
gland-derived SZ95 sebocytes selectively inhibited lipid synthesis (sebum production) and altered the expression profiles
of multiple genes that are involved in cellular lipid homeostasis159.
In addition to TRPV1 and TRPV3, other TRP channels (for example, TRP cation channel subfamily C, member 1 (TRPC1),
TRPC4, TRPV4, TRPV6, TRP cation channel subfamily A, member 1 (TRPA1) and TRP cation channel subfamily M,
member 8 (TRPM8)) have been identified in skin keratinocytes, where they are probably involved in the differentiation —
and malignant transformation — of keratinocytes and barrier formation. Intriguingly, several skin pathologies have
altered TRP channel expression. For example, basal cell carcinoma cells lack both TRPC1 and TRPC4 expression160.
Conversely, TRPC1 is overexpressed in the skin of patients with Darier’s disease161. TRPV4 seems to promote the
development and maturation of intercellular junctions in the epidermis85, thus topical TRPV4 agonist preparations may
represent a novel approach in the treatment of acne vulgaris. Stimulation of TRPA1 affects the expression profile of
genes that are involved in the control of keratinocyte proliferation and differentiation162. TRPV6 participates in the differ‑
entiation-stimulatory effects of 1,25‑dihydroxyvitamin D3 by increasing Ca2+ entry163. At present, it is unclear how specific
these effects are, as dramatic increases in calcium concentration are likely to affect the proliferation and differentiation of
skin cells. Last, decreased and/or faulty TRPM7 production leads to impaired melanocytic differentiation164, which can
result in vitiligo.
procedure is poorly tolerated and has therefore not to these irritants27–29,98. Thus, emerging data from animal
been widely adopted. The explanation for the efficacy models largely indicate that TRPA1 is the sole effector
of capsaicin desensitization therapy remains elusive. The of sensory neuron activation and respiratory irritation
beneficial effects of capsaicin may paradoxically extend reflexes that are triggered by acute exposure to a range
beyond its actions on TRPV1, in that it may functionally of respiratory irritants. One noteworthy exception is
inactivate the entire TRPV1‑expressing neuron5. Such nicotine, which activates sensory neurons by acting at
neurons express many other gene products in addition both TRPA1 and nicotinic acetylcholine receptors99.
to TRPV1, including the related polymodal nocisensor Further clarification is required regarding the com-
TRPA1 (see below). plex interplay between these two mechanisms in vivo.
TRPA1 is necessary for increases in the Penh (enhanced
TRPA1. Many of the irritants that activate TRPA1 are pause) respiratory measurement caused by intrana-
air pollutants that are produced by the combustion of sal nicotine 99; however, similar provocations pro-
materials (including tobacco products) that cause pro- duce robust respiratory irritation in TRPA1‑deficient 
nounced cutaneous, ocular and respiratory irritation in mice28.
humans. Several classes of anaesthetic molecules — Although further studies will reveal the contribu-
including lidocaine, propofol, etomidate and volatile tion of TRPA1 to the overall respiratory pathology that
gaseous anaesthetics — also act as TRPA1 agonists96. is caused by chronic exposure to hazardous irritants in
Although these data raise the possibility that anaesthesia humans, existing data from mice already demonstrate
may paradoxically increase postoperative pain, the more the role of TRPA1 in allergic airway inflammation. Mice
immediate impact of these data is the identification of that either lacked TRPA1 or were pretreated with the
TRPA1 as a possible mediator of the respiratory com- TRPA1 blocker HC‑030031 were protected from air-
plications of gaseous anaesthetics, which can include way inflammation (both in bronchoalveolar lavage and in
coughing and laryngospasms. In support of this hypoth- lung tissue) and bronchial hyperreactivity in response
esis, the TRPA1 blocker HC‑030031 has been shown to to acetylcholine. Transcription of the gene product for
prevent desflurane-induced increases in airway resist- the gel-forming mucin, MUC5AC, was also reduced100.
ance in guinea pigs26. This suggests that HC‑030031 prevented gene transcrip-
Additional hazardous irritants — which include iso- tion, although no measurement of the protein (that is,
cyanates, ozone, chlorine and cigarette smoke extracts the gene product) was performed. Importantly, knock-
— activate overexpressed TRPA1 and cause pulmo- ing out TRPV1 did not alter any of these parameters100,
nary nociceptor activation, respiratory irritation and/ thus providing evidence that TRPA1 has a distinct role
or neurogenic inflammation in a TRPA1‑dependent in this model of allergic disease. In addition, TRPA1 has
manner 25,27–29,97. These molecules are broadly toxic, and been implicated in neurogenic inflammation of the
exposure to them causes marked symptoms and injury airway caused by the acetaminophen (paracetamol)
in human airways. Perhaps surprisingly, interruption metabolite N‑acetyl‑p-benzoquinone imine in sev-
of TRPA1 function in rodents — via gene disruption eral species of small rodents101. These compelling data
or pharmacological blockade — nearly abolishes demonstrate that TRPA1 can contribute to both res-
the activation of sensory neurons and/or respiratory piratory reflexes and inflammation in laboratory-based
reflexes, including coughs produced by acute exposure animal models.
© 2011 Macmillan Publishers Limited. All rights reserved
 REVIEWS

TRPC and TRPV channels in airway structural and lungs from these animals have marked deficits in arterial
inflammatory cells. Several TRP channels are expressed oxygen saturation following airway instillation of saline
in bronchial and/or vascular smooth muscle. TRP cat- to produce regional ventillatory failure102. Moreover,
ion channel subfamily C (TRPC) has functional roles in a SNP (–254C→–254G) in the promoter region of the
the pulmonary vasculature, particularly with regard to gene encoding TRPC6 has been linked to idiopathic
responses to hypoxia. Regional alveolar hypoxia redirects pulmonary arterial hypertension103. Consistent with this
blood flow to well-oxygenated areas. This reflex mecha- finding, pulmonary arterial smooth muscle cells from
nism is impaired in TRPC6‑knockout mice, as ex vivo patients with idiopathic pulmonary arterial hyperten-
sion had considerably higher levels of the TRPC6 pro-
tein, higher resting levels of cytosolic Ca2+ and larger
8CICNUGPUQT[PGTXGVGTOKPCNU #KTYC[UOQQVJOWUENG 1‑oleyl‑2‑acetyl-sn-glycerol (OAG)-dependent cationic
r642#CPF6428 r642%CPF6428 currents than samples from control subjects103.
r(WPEVKQPUFGRQNCTK\CVKQPCEVKQP r(WPEVKQPUEQPUVTKEVKQP Smooth muscle cells in diseased airways typically dis-
RQVGPVKCNHQTOCVKQPKPKVKCVKQPQH CKTȯQYQDUVTWEVKQP
UGPUCVKQPUCPFTGȯGZGU play abnormalities in contraction and/or proliferation.
5GPUCVKQPU
Although bronchodilators are efficacious therapies that
8CIWUPGTXGU
r7TIGVQEQWIJ are capable of reversing airflow obstruction, treatments
r%JGUVVKIJVPGUU that reduce contractility and pathological remodelling of
r&[URPQGC
CKTJWPIGT airway smooth muscle remain targets for active investi-
%05FGRGPFGPVTGȯGZGU gation. Following incubation with the inflammatory
r%JCPIGUKPTGURKTCVQT[
RCVVGTP cytokine tumour necrosis factor, human airway smooth
r%QWIJ muscle cells had marked changes in Ca2+ homeostasis
r2CTCU[ORCVJGVKETGȯGZ that are accompanied by increased expression of the
CKTȯQYNKOKVCVKQP
r%JCPIGUKPCKTYC[DNQQFȯQY TRPC3 protein104. Moreover, enhanced acetylcholine-
induced elevations in cytosolic Ca2+ in human airway
smooth muscle cells are blocked by RNA silencing of
TRPC3. These data are consistent with studies in mice
#KTYC[XCUEWNCVWTG with allergen-induced airway inflammation; in these
r642%CPFQT642%!

GZVTCCNXGQNCT6428
CNXGQNCT
studies TRPC3‑specific antibodies inhibited non-selec-
r(WPEVKQPUXCUQEQPUVTKEVKQP tive cation conductances and restored resting membrane

642%KPETGCUGUKPGZVTC potentials of airway smooth muscle cells to values that
CNXGQNCT
642%UCPF
CNXGQNCT
6428
were more hyperpolarized and consistent with con-
XCUEWNCT #NXGQNCTOCETQRJCIGU trols105. Compensatory elevation of TRPC3 expression
r6428CPF6428
RGTOGCDKNKV[
r(WPEVKQPUUVKOWNCVKQP occurs in Trpc6–/– mice, which may explain why these
QHRJCIQE[VQUKU
6428 mice have enhanced airway reactivity in response to a
'PFQVJGNKWO 405CPFQT415 muscarinic agonist, despite displaying reduced inflam-
85/%U RTQFWEVKQP
6428
matory parameters in bronchoalveolar lavage fluid106.
Figure 5 | Diverse roles of TRP channels in the pathophysiology of the mammalian
TRPV4 has also been proposed to contribute to Ca2+
respiratory tract. Although transient receptor potential0CVWTG4GXKGYU^&TWI&KUEQXGT[
(TRP) channels generally mobilization in airway smooth muscle107. This function
increase intracellular Ca2+ concentrations and/or depolarize membrane potentials, their of TRPV4 is one possible mechanism that may explain
varied expression patterns and sensitivity to agonists result in considerable functional the genetic association between multiple SNPs in the
diversity. For instance, in vagal sensory nerve terminals, noxious chemical and physical gene encoding TRPV4 and chronic obstructive pulmo-
stimuli activate TRP cation channel subfamily A, member 1 (TRPA1) and TRP cation nary disease108, although the function of TRPV4 in the
channel subfamily V, member 1 (TRPV1) to produce nerve activation, which initiates respiratory tract extends beyond airway smooth muscle
reflexes and critically regulates sensations, as shown in the figure. In airway smooth responsiveness. Indeed, the TRPV4 gene containing the
muscle cells, functional TRP cation channel subfamily C, member 3 (TRPC3) and TRPV4 chronic obstructive pulmonary disease-associated P19S
channels have been identified and these are thought to contribute to constriction that
SNP displays gain-of-function characteristics in human
leads to airflow obstruction, as these channels are Ca2+-permeable and Ca2+ is a
necessary mediator of smooth muscle constriction. TRPC6, which is present in airway
airway epithelial cells, where the disease-associated SNP
vascular smooth muscle cells (VSMCs), can mediate vessel constriction to reduce blood has been shown to increase Ca2+ influx and secretion of
flow. Several other TRPCs have been identified in endothelial cells of larger matrix metalloproteinase 1 in response to diesel exhaust
(extra-alveolar) blood vessels within the lung, where their activation can increase fumes109.
vascular permeability and cause fluid to leak into interstitial spaces between The most striking manifestation of TRPV4 biology in
vessels. Activation of endothelial TRPV4 also increases vascular permeability, although the lung occurs in the alveolar septae. In isolated, per-
this increase is specific to the small blood vessels that supply the alveoli of lungs. TRPV4 fused lungs in mice, activation of TRPV4 by elevated
has also been identified on alveolar macrophages, where its activation triggers the vascular pressure110 or injurious high-pressure mechani-
production of toxic reactive oxygen species (ROS) and reactive nitrogen species (RNS). cal ventilation111 caused extravascular leakage of fluid,
TRPV2 channels are also present on alveolar macrophages, as well as several other
as reflected by increases in the filtration coefficient (Kf)
macrophage populations, where their activation stimulates phagocytosis of foreign
material. Although these data have largely been generated in laboratory animal species,
of lung fluid via extravascular leakage. Consistent with
clinical data already exist that support a role of TRPA1 and TRPV1 in respiratory sensory these findings, intravenous administration of the TRPV4
nerves, as acute exposure to agonists of either channel (notably, tear gases for TRPA1 and agonist GSK1016790A causes circulatory collapse that
pepper sprays for TRPV1) can cause intense, incapacitating respiratory irritation in is characterized by the failure of the alveolar septal bar-
humans. CNS, central nervous system. rier 112. Although the same study also demonstrated that

NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 | 613

© 2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
Bronchoalveolar lavage
A procedure in which
inflammatory cells and other
materials within the airway
lumen are collected via
repeated washings.
Alveoli
Distal regions of the lung in
which a thin barrier between
airspaces and capillaries allows
for gas exchange.
Filtration coefficient (Kf)
A measurement that is used to
reflect the permeability of the
pulmonary vasculature to fluid.
Autosomal dominant
brachyolmia
A disorder that is typified by
short stature, a short trunk and
curved spine.
Spondylometaphyseal
dysplasia
A skeletal disorder that is
typified by short stature and
abnormalities in the vertebrae
and tubular bones.
Charcot–Marie–Tooth
disease
Also known as hereditary
motor and sensory neuropathy.
This disease, named after the
three doctors who first
identified it, is one of the most
common inherited
neuropathies. Symptoms
include weakness, motor
atrophy and foot deformities.
Focal segmental
glomerulosclerosis
A disease that is typified by
glomerular scarring, which
results in proteinuria, oedema
and the eventual need for
dialysis.
Familial episodic pain
syndrome
A rare disorder that is typified
by periods of severe pain in the
trunk and upper body.
Episodes are typically triggered
by cold temperatures and/or a
low energy state brought about
by hunger or fatigue.
614 | AUGUST 2011 | VOLUME 10 www.nature.com/reviews/drugdisc
GSK1016790A can produce dramatic deformation of
cultured human endothelial cells, it was recently dem-
onstrated that TRPV4 that is expressed on alveolar mac-
rophages can have a crucial role in ventilator-induced
injury in isolated lungs of mice113. Although these data
suggest that discerning the exact mechanism (or mecha-
nisms) of TRPV4‑mediated lung injury may be challeng-
ing, they highlight the contribution of TRPV4 activation
to pulmonary oedema that is caused by aberrant vascu-
lar or airway pressures.
TRP channels and human genetic diseases
Mutations in at least six of the 28 members of the TRP
channel superfamily are associated with genetic dis-
eases in humans (reviewed in REFS 3,4). The diversity of
pathologies caused by TRP channel dysfunction high-
lights the range of roles TRP channels have in normal
physiology and underscores the importance of calcium
signalling in various systems. Some of the rare muta-
tions may also point to a more general role for TRP
channels in these pathologies. In situations in which a
gain-of-function mutation underlies the pathology of a
TRP channelopathy, the potential utility of an antago-
nist is evident; however, TRP channel agonists could
also have therapeutic benefits in situations in which
one allele is intact or the mutation reduces the probabil-
ity of the channel being open but leaves TRP channel
function intact.
TRPV4. Mutations in TRPV4 cause several divergent
heritable diseases that affect diverse systems. Genetic
deletion of Trpv4 in mice leads to a substantial increase
in bone mass and reduced bone loss owing to lack of
weight bearing114. TRPV4 also has an important role
in bone resorption and osteoclast differentiation115. In
line with this finding, more than 19 autosomal domi-
nant human mutations in TRPV4 are associated with
skeletal dysplasias116. In two families, TRPV4 mutations
(R616Q and V620I) that caused profound increases in
levels of current in heterologous systems led to autoso-
mal dominant brachyolmia117. Other mutations in TRPV4
lead to additional skeletal disorders of varying severity,
including spondylometaphyseal dysplasia118. Both mild
and lethal forms of metatrophic dysplasia are also due
to mutations in TRPV4 that increase channel activity
in vitro116–118.
Mutations in TRPV4 have also been linked to periph-
eral neuropathies, including hereditary motor and
sensory neuropathy type 2C (also known as Charcot–
Marie–Tooth disease type 2C), scapuloperoneal spinal
muscular atrophy and congenital distal spinal muscular
atrophy 119,120. In five families, three separate missense
mutations were identified that altered arginine residues
in the amino terminal ankyrin repeat domains119,120.
These mutations appear to be gain-of-function muta-
tions120, although they have also been characterized as
loss-of-function mutations that are potentially caused
by the decreased expression of functional channels119.
These discrepancies need to be resolved by further stud-
ies, as the cellular context in which the TRP channel is
expressed may influence the function of the mutated
© 2011 Macmillan Publishers Limited. All rights reserved
TRP channels. Collectively however, these data suggest
a potential value for TRPV4 modulators in the treatment
of heritable disorders, including skeletal dysplasias and
sensory and motor neuropathies.
TRPP2. Mutations in the genes encoding two proteins,
polycystic kidney disease 1 (PKD1) and TRP cation
channel polycystin subfamily 2 (TRPP2; also known as
PKD2), are causative factors in polycystic kidney dis-
ease and are responsible for ~85% and ~15% of cases,
respectively 121. The proteins encoded by these genes
are thought to interact with each other in vivo to form
a cation channel–receptor complex that is involved in
pressure sensing in the cilia122. The exact role of each
protein is unclear, but the ratio of PKD1 expression to
TRPP2 expression seems to be crucial for normal pres-
sure sensing 123. These findings may help to explain
some of the cardiovascular abnormalities (for example,
hypertension and aortic aneurysm) that are observed in
polycystic kidney disease. In addition, they highlight the
challenge of restoring normal function in patients via a
TRPP2 modulator.
TRPC6. Mutations in TRPC6 also lead to kidney dys-
function. A large family was analysed and it was discov-
ered that a single point mutation (P112Q) in TRPC6 was
sufficient for causing focal segmental glomerular sclero-
sis124. Subsequently, additional mutations in TRPC6 that
led to nephrosis were identified125, and there is increas-
ing interest in TRPC6 as a potential target for the therapy
of acquired kidney diseases. When they are expressed
in heterologous systems, several of these mutated TRP
channels show substantial increases in the amplitude
of the current 126 and they implicate calcium handling
in glomerular disease. One possible downstream effect
of overactive TRPC6 is the increased activation of the
nuclear factor of activated T cells (NFAT)–calcineurin
signalling pathway 127.
TRPA1. Studies on a family have revealed an autoso-
mal dominant mutation in the fourth transmembrane
domain of TRPA1 that underlies familial episodic pain
syndrome43: this is the first and as yet only example of
a TRP channel mutation that is implicated in a human
pain syndrome. The recombinantly expressed familial
episodic pain syndrome mutant N855S TRPA1 carries
more current than wild-type TRPA1 at negative poten-
tials, although maximal current responses to reactive
chemical agonists appear to be unaltered43. Not only do
these data highlight the relevance of the modulation of
TRPA1 at cold temperatures in humans but they also
suggest a possible connection between cellular energetics
and TRPA1 function.
TRPM6. Like the closely related TRPM7 channel,
TRPM6 is distinguished from other TRP channel family
members because it has a large carboxyl terminal pro-
tein kinase domain (reviewed in REF. 3). Loss-of-function
mutations in TRPM6 underlie inherited autosomal
recessive hypomagnesaemia with secondary hypocalcae-
mia (reviewed in REF. 4). Several mutations, including

Mucolipidosis type IV
A lysosomal storage disorder.
Symptoms typically present
during the first year of life and
affected individuals suffer from
psychomotor retardation,
ophthalmological
abnormalities and anaemia.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 | 615
deletion of exons, point mutations, deletion mutations
and premature stop codons can lead to the disease128–130.
These findings raise the possibility that compounds that
increase TRPM6 activity could be useful in the treatment
of both inherited and sporadic hypomagnesaemia.
TRPML1. Mutations in TRP cation channel mucolipin
subfamily 1 (TRPML1; also known as mucolipin 1) cause
mucolipidosis type IV. Subsequent studies on the func-
tion of TRPML1 have indicated that it is an intracellular
protein that is localized to the endosome and lysosome,
and is responsible for iron transport independently
of the divalent metal transporter 1 (REF. 131). Disease-
associated mutations in TRPML1 compromise its ability
to transport iron, and this occurs in a manner that corre-
lates well with disease severity 131. These data suggest that
molecules that improve the function of TRPML1 could
be useful treatments for individuals with mucolipidosis
type IV. However, screening for such compounds using
traditional fluorescent assays and electrophysiological
techniques is difficult given the intracellular localiza-
tion of the channel.
TRP channels in the brain
Many TRP channels are expressed by brain tissue; some
are expressed at high levels (for example, TRPC3 and
TRPC5), whereas others are expressed at low levels
(for example, TRPV1). The function of these channels
remains to be elucidated, but there is evidence that sev-
eral TRP channels may contribute to neuronal excit-
ability and neurotransmitter-mediated signalling in
the brain.
TRPV1. There is controversy surrounding the expres-
sion and role of TRPV1 in the brain. Some studies report
that TRPV1 is widely expressed throughout the whole
neuroaxis of the rat (albeit at much lower levels than in
sensory neurons; reviewed in REF. 132). However, recent
research — that relies on a powerful combination of
reporter mice, in situ hybridization, electrophysiological
recordings and calcium imaging — suggests that TRPV1
expression is restricted to very few regions of the brain,
most notably the caudate nucleus of the hypothalmus133.
Consequently, additional research will need to be car-
ried out to explain the differences that have been noted
in the behavioural responses between wild-type and
Trpv1–/– mice.
Trpv1–/– mice adapt more easily than their wild-type
littermates to aversive light, and they explore the open
arm of the elevated maze more freely; these results are
indicative of a reduced unconditional fear response in
Trpv1–/– mice134. Furthermore, Trpv1–/– mice exhibit
less freezing than wild-type mice in auditory fear con-
ditioning assays134. These findings imply that TRPV1
antagonists have therapeutic potential as novel anxio-
lytic agents. Notably, TRPV1 is present in dopaminergic
neurons in the basal ganglia and it was speculated that
malfunction of TRPV1 may be involved in the patho-
genesis of Parkinson’s disease135. Some studies have also
reported on the presence of TRPV1 in the hippocam-
pus136 and nucleus accumbens137; TRPV1 may modulate
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
the strength of synaptic transmission in these regions.
Future behavioural studies that directly compare selec-
tive TRPV1 antagonists with differential central nervous
system penetrances are needed to elucidate the role of
TRPV1 in brain function.
TRPC3. TRPC3 is the most abundant TRP channel of
the TRPC subfamily in cerebellar Purkinje cells. Like
TRPC6 and TRPC7, TRPC3 is activated by diacyl-
glycerol, and Gq-coupled GPCRs are likely to be crucial
regulators of channel activity in vivo (reviewed in REF. 3).
In addition, receptor tyrosine kinases activate TRPC3
in vitro and brain-derived neurotrophic factor-mediated
survival of cerebellar granular cells depends on func-
tional TRPC3 expression138.
Trpc3–/– mice show considerably attenuated inward
currents in response to activation of metabotropic glu-
tamate receptor 1 (mGluR1), which is a GPCR that
is thought to be upstream of TRPC3; this finding is
consistent with the role of TRPC3 in the cerebellum.
Trpc3–/– mice also display impairments in walking behav-
iour, although — as predicted — the TRPC3‑knockout
phenotype is less severe than the ataxia observed in
mGluR1–/– animals139.
A screen in chemically mutagenized mice also
identified a crucial role for TRPC3 in Purkinje cells.
Moonwalker mice — mice with a T635A mutation in
Trpc3 — showed progressive Purkinje cell degeneration
and ataxia140. In cerebellar slices, this mutation resulted
in a higher amplitude of currents in response to low
concentration of an mGluR1 agonist 140. Taken together,
these data indicate that TRPC3 channels have an impor-
tant role in synaptic transmission in cerebellar Purkinje
cells and in the survival of these cells. Identification of
selective pharmacological agents will be useful for deter-
mining whether TRPC3 has a broader role in ataxia.
TRPC5. High levels of TRPC5 are expressed in the hip-
pocampus and amygdala141. Trpc5–/– mice show less
innate fear behaviour than their wild-type littermates
in an open-field test, an elevated plus maze test and a
nose bumping assay 141. In addition, their conditioned
fear memory is unaffected in a single fear conditioning
paradigm141. These data are consistent with observations
made in brain slice recordings in which Trpc5–/– mice
showed normal membrane excitability and synaptic
function but reduced synaptic responses to activation
of mGluRs and cholecystokinin (CCK) receptors141.
These data provide a potential link between TRPC5
and the CCK4 signalling pathway, the activation of
which induces anxiety behaviours in rodents and
humans. This suggests that TRPC5 antagonists might
be useful as anxiolytic agents. Additional work will be
required to determine whether a pharmacological agent
can recapitulate the effects of genetic deletion. Further
analysis of the role of TRPC5 in learning and memory
is also warranted.
TRPC5 may also have an important role in the cal-
cium-mediated guidance of neuronal growth cones142.
Further in-depth studies on the brain architecture
in developing Trpc5 –/– mice and experiments that
REVIEWS
examine receptor-activated neurite extension in brain
slices should help to clarify the contribution of TRPC5
to axonal pathfinding.
TRPM2 and TRPM7. In the brain, TRPM2 is expressed
by neurons and microglia. Consistent with the concept
that TRPM2 functions as a redox sensor, Trpm2–/– mice
are protected against various pathologies related to oxi-
dative stress, including the focal ischaemia model of
stroke143. The TRPM2 gene is also a candidate risk fac-
tor gene for bipolar disorder 144. Knockdown of TRPM7
reduces cell death that is caused by oxygen- and/or glu-
cose deprivation in isolated neuronal cultures145, which
implies that TRPM7 antagonists may have a role in the
treatment of stroke.
Other diseases
In addition to the therapeutic areas described above,
TRP channels have been implicated in various other
diseases. Although some are not reviewed here, we dis-
cuss the most noteworthy findings, in our opinion, for
therapeutic targeting.
Cancer. Several TRP channels have been linked to can-
cer, some as markers of biological behaviour (such as
aggressive versus indolent phenotypes), whereas oth-
ers could be putative therapeutic targets (reviewed in
REF. 146). TRPM8 is a prime example of a marker that is
also a target. TRPM8 is overexpressed in prostate can-
cer, and its level of expression correlates with tumour
severity 147. At the same time, the TRPM8 agonist men-
thol reduces the proliferation and viability of prostate
cancer cell lines148. Notably, the synthetic TRPM8 ago-
nist D‑3263, which reduces benign prostatic hyperplasia
in rats, is in clinical trials (ClinicalTrials.gov identifier:
NCT00839631). The structure of this compound has not
yet been published. As patients with benign prostatic
hyperplasia often have prostate cancer, they could con-
ceivably benefit from TRPM8 agonist treatment, which
would both improve bladder function and reduce the
risk of cancer.
Cardiovascular diseases. TRPM4, which is activated by
(but not permeable to) Ca2+ ions, regulates many aspects
of cardiovascular function (reviewed in REF. 3). Within the
cerebral arteries of rats, antisense oligonucleotide deple-
tion of TRPM4 reduces the potential depolarization of the
myocyte membrane and reduces myogenic vasoconstric-
tion caused by elevated intraluminal pressure149. TRPM4
has also been implicated in human cardiac conduction
disorders150, as mutations in the channel that resulted in a
net gain-of-function have been identified in several fami-
lies that had a block of cardiac electrical conduction151.
Loss of TRPM4 expression is, however, not categorically
cardioprotective as Trpm4–/– mice are hypertensive152.
Mechanistic investigations have revealed that this is due
to increased adrenal catecholamine release rather than
direct cardiac or vascular effects152.
Overexpression of TRPC6 and calcineurin-NFAT
signalling are associated with angiotensin II‑induced
cardiac hypertrophy, and the expression of a dominant
616 | AUGUST 2011 | VOLUME 10 www.nature.com/reviews/drugdisc
© 2011 Macmillan Publishers Limited. All rights reserved
negative Trpc6 transgene renders mice less susceptible
to hypertrophy 153. Consequently, there is substantial
interest in assessing the utility of TRPC6 antagonists in
various models of cardiovascular disease. Owing to the
dramatic upregulation of TRPC3 following genetic dele-
tion of TRPC6, selective TRPC6 antagonists are needed
to probe the utility of TRPC6 as a therapeutic target.
Metabolic disorders. Genetic deletion of TRPM5, a
known taste sensor, results in impaired glucose toler-
ance in mice154. This phenotype may be due to the loss
of high-frequency calcium oscillations in pancreatic
β-cells155, although the effects of TRPM5 deletion can-
not be accounted for by simple changes in membrane
potential. In animal models, inactivation of TRPV1
by genetic or pharmacological manipulation has been
shown to protect against the development of type 1 dia-
betes and improve glucose tolerance in type 2 diabetes
(reviewed in REF. 156). In Trpv1–/– mice, both increased13
and decreased157 body fat was reported, therefore the
role of TRPV1 in the regulation of body weight remains
controversial.
Conclusions
The recent expansion of research into TRP channels
has resulted in the identification of numerous potential
drug targets beyond TRPV1, and has elucidated roles
for TRP channels in diverse therapeutic areas includ-
ing pain, pulmonary indications, oncology, neurology
and genetic disorders. Interest is mounting as a result of
emerging data from animal models, human genetic dis-
orders and, in some cases, compounds entering clinical
trials. Indeed, at this early stage, with very limited clini-
cal data available regarding the effects of small-molecule
blockade of a single TRP channel (TRPV1), it is decep-
tively easy to speculate on the therapeutic potential —
or the potential to cause mechanism-based toxicological
liabilities — of TRP channel modifiers. Several questions
remain unanswered, and are listed below.
How predictive are the animal models that are used
to test TRP channel modulators? Available data largely
suggest that recombinant human TRP channels respond
to the same sorts of stimuli as their laboratory animal
orthologues (for example, rat, mouse and human TRPM8
are all activated by menthol and cool temperatures).
Moreover, acute behavioural effects of known TRP chan-
nel modulators tend to be similar between humans and
laboratory animals (for example, topical capsaicin causes
nocifensive behaviour and swelling when it is applied to
rodent or human skin), even if the molecular identity
of the protein (or proteins) underlying the response in
humans remains unconfirmed. Although most TRP
channels have not been studied to this extent, in vitro
differences between mammalian orthologues to date are
generally quantitative (for example, differences in the
potency of activating ligands) rather than qualitative.
Will target validation generated via genetic means be
predictive of blocker effects? Potent and selective small-
molecule modulators of TRP channels are continuing
 REVIEWS

to emerge. These tools are vital for advancing the field,
as acute blockade does not always mimic the protec-
tive and/or deleterious effects of genetic removal.
Although these two methods often correlate well, a
number of notable exceptions have occurred. A prime
example is TRPV1. Some TRPV1 antagonists cause
hyperthermia, which has necessitated the withdrawal
of these compounds from clinical trials (reviewed in
REF. 14), yet Trpv1–/– mice have normal body tempera-
tures9,11. Furthermore, the TRPV1 antagonist GRC‑6211
improves bladder capacity 65; by contrast, Trpv1–/– mice
show spotty incontinence60. Other examples include
TRPV4 (for example, the TRPV4 blocker HC‑067047
does not alter thermal selection behaviour or water
consumption in mice67) and TRPA1 (for example, block-
ade but not knockout of TRPA1 inhibits CFA-induced
mechanical hyperalgesia34).
Will TRP channel modulators be safe and well toler-
ated in humans? As with all novel targets, questions exist
regarding the potential mechanism-based toxicological
liabilities of TRP channel modulators. Speculation in this
area is rampant, owing at least in part to the paucity of
empirical evidence regarding the safety and tolerability
of modulators of any of these targets other than TRPV1.
Even in the case of TRPV1, in which several structur-
ally unrelated molecules have been dosed in patients and
dose-limiting effects that appear to be mechanism-based
(such as alterations in thermosensation16,17 and/or ther-
moregulation10,16,17) have been consistently observed, the
magnitude of these effects has varied considerably owing
to factors that are only partially understood.
Will an agonist or an antagonist be therapeutically use-
ful? The answer to this question is rarely as obvious as it
seems: in the pain area, both agonists and antagonists of
TRPV1 are being evaluated in clinical trials, and the first
approved TRPV1 modulator is capsaicin, which robustly
activates the channel (reviewed in REF. 5). Similar ques-
tions exist for TRPM8, as both agonists and antagonists
are being pursued for the treatment of pain (reviewed
in REF. 7). Clearly, the answer to this question will vary
depending on the nature of the disease state and the TRP
channel (or channels) that are involved.
The answers to the above questions will help to
determine the answer to the most pressing question in
the TRP channel-related field: will blocking (or other-
wise modulating) TRP channels ameliorate established
human disease? This answer will only be obtained after
long-term clinical studies have been carried out in
patients. However, the broad and pronounced links to
pathophysiological processes that have been revealed by
extensive preclinical target validation and human genetic
studies — in addition to the relatively high chemical
tractability of the TRP superfamily of ion channels —
provide strong cause for optimism.

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REVIEWS
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Acknowledgements
We would like to thank B. Nilius for reading the manuscript and
providing useful comments, and M. Trevisani for his help in com-
piling the TRPV1 antagonist clinical trials database.
620 | AUGUST 2011 | VOLUME 10 www.nature.com/reviews/drugdisc
Competing interests statement
The authors declare competing financial interests: see Web
version for details.
FURTHER INFORMATION
ClinicalTrials.gov website: http://www.clinicaltrials.gov
Daewoong Pharmaceutical website: http://www.daewoong.
co.kr/www_pharm/english_new/aboutus/whatsnews_view.
asp?idx=60652
Drugs.com website: http://www.drugs.com/clinical_trials/
anesiva-phase‑3‑trial-adlea-meets-primary-endpoint-
significantly-reduce-pain-after-total-knee‑6536.html
Drugs.com website: http://www.drugs.com/newdrugs/
neurogesx-receives-fda-approval-qutenza-
capsaicin‑8‑patch-postherpetic-neuralgia-phn‑1772.html
Glenmark Pharmaceuticals website: http://www.
glenmarkpharma.com/GLN_NWS/pdf/GRC_6211.pdf
Japan Tobacco — Clinical Development of Pharmaceuticals
(29 July 2010): http://www.jt.com/investors/results/
pharmaceuticals/pdf/P.L.20100729_E.pdf
PharmEste website: http://www.pharmeste.com/home.
asp?op=interna&id=2&id_pag=10&tit=Pipeline
Sanofi website: http://en.sanofi.com/research_innovation/
rd_key_figures/rd_key_figures.asp
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