Key Points
-
The role of transient receptor potential (TRP) channels is best understood in the pain area. As TRP channels are expressed on peripheral nociceptors, where pain is generated, it is hoped that TRP channel blockers will be devoid of the side effects that limit the use of analgesic agents that act on the central nervous system.
-
Several TRP cation channel subfamily V, member 1 (TRPV1) antagonists have advanced to clinical trials, but their side effects (which include hyperthermia and impaired noxious heat detection) have prevented any compounds from progressing beyond Phase II clinical trials.
-
TRPV3 antagonists have shown efficacy in models of neuropathic and inflammatory pain, and one antagonist has entered Phase I clinical trials.
-
An autosomal dominant mutation in the gene that encodes TRP cation channel subfamily A, member 1 (TRPA1) causes familial episodic pain syndrome. Indeed, TRPA1 antagonists have been shown to reduce cold hypersensitivity in rodent models of neuropathic pain without altering normal cold sensation in naive animals.
-
Several TRP channels (such as TRPV1, TRPV4 and TRP cation channel subfamily M, member 8 (TRPM8)) are expressed in the urinary bladder, where they presumably function as sensors of stretch and chemical irritation. TRPV1 and TRPV4 antagonists improve bladder function in rodent models of cystitis.
-
Populations of non-neuronal cells within the skin express many different types of TRP channels that are implicated in the regulation of several key cutaneous functions including skin-derived pruritus, proliferation, differentiation and inflammatory processes.
-
TRPA1 and TRPV1 serve as polymodal sensors in the mammalian respiratory tract that integrate varied inflammatory, oxidant and hazardous irritant stimuli to produce noxious sensations (for example, breathlessness, the urge to cough and nasopharyngeal pain) and respiratory reflexes such as coughing.
-
Several TRP channels — including members of TRP cation channel subfamily C (TRPC) and TRPV — influence the process of gas exchange by regulating airflow, blood flow and airway permeability.
-
Mutations in at least six of the 28 members of the TRP channel superfamily are associated with heritable genetic diseases in humans. These mutations have implicated TRP channels in many pathophysiological states and expanded our understanding of the physiological role of these channels.
-
The role of TRP channels in the brain remains to be elucidated, but it seems to be clear that some members of the superfamily are involved in neuronal excitability and neurotransmitter release. Genetic deletion of TRPC5 leads to an anxiolytic phenotype, whereas a point mutation in TRPC3 leads to ataxia.
-
TRP channels also serve important functions in other diseases that are not fully explored in this Review. For example, cancer and metabolic diseases will be particularly interesting to watch in the future.
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Patapoutian, A., Tate, S. & Woolf, C. J. Transient receptor potential channels: targeting pain at the source. Nature Rev. Drug Discov. 8, 55–68 (2009).
Szallasi, A., Cortright, D. N., Blum, C. A. & Eid, S. R. The vanilloid receptor TRPV1, 10 years from channel cloning to antagonist proof-of-concept. Nature Rev. Drug Discov. 6, 357–372 (2007).
Wu, L. J., Sweet, T. B. & Clapham, D. E. International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol. Rev. 62, 381–404 (2010).
Nilius, B. & Owsianik, G. Transient receptor potential channelopathies. Pflugers Arch. 460, 437–450 (2010).
Szallasi, A. & Blumberg, P. M. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol. Rev. 51, 159–212 (1999).
Fanger, C. M., del Camino, D. & Moran, M. M. TRPA1 as an analgesic target. Open Drug Discov. J. 2, 63–69 (2010).
McKemy, D. D. Therapeutic potential of TRPM8 modulators. Open Drug Discov. J. 2, 80–87 (2010).
Everaerts, W., Nilius, B. & Owsianik, G. The vanilloid transient receptor potential channel TRPV4: from structure to disease. Prog. Biophys. Mol. Biol. 103, 2–17 (2010).
Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).
Gavva, N. R. et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136, 202–210 (2008).
Iida, T., Shimizu, I., Nealen, M. L., Campbell, A. & Caterina, M. Attenuated fever response in mice lacking TRPV1. Neurosci. Lett. 378, 28–33 (2005).
Toth, D. M. et al. Nociception, neurogenic inflammation and thermoregulation in TRPV1 knockdown transgenic mice. Cell. Mol. Life Sci. 11 Nov 2010 (doi:10.1007/s00018-010-0569-2).
Garami, A. et al. Thermoregulatory phenotype of the Trpv1 knockout mouse: thermoeffector dysbalance with hyperkinesis. J. Neurosci. 31, 1721–1733 (2011).
Romanovsky, A. A. et al. The transient receptor potential vanilloid-1 channel in thermoregulation: a thermosensor it is not. Pharmacol. Rev. 61, 228–261 (2009).
Gavva, N. R. et al. Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade. J. Pharmacol. Exp. Ther. 323, 128–137 (2007).
Rowbotham, M. C. et al. Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial. Pain 152, 1192–1200 (2011).
Krarup, A. L. et al. Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain. Aliment. Pharmacol. Ther. 33, 1113–1122 (2011). This was the first report of a TRPV1 antagonist that had clinical efficacy in a painful disease state without causing significant adverse effects.
Lehto, S. G. et al. Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2, 3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(tri fluoromethyl)phenyl)-acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats. J. Pharmacol. Exp. Ther. 326, 218–229 (2008).
Chizh, B. A. et al. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain 132, 132–141 (2007).
Knotkova, H., Pappagallo, M. & Szallasi, A. Capsaicin (TRPV1 agonist) therapy for pain relief: farewell or revival? Clin. J. Pain 24, 142–154 (2008).
Noto, C., Pappagallo, M. & Szallasi, A. NGX-4010, a high-concentration capsaicin dermal patch for lasting relief of peripheral neuropathic pain. Curr. Opin. Investig. Drugs 10, 702–710 (2009).
Li, H., Wang, S., Chuang, A. Y., Cohen, B. E. & Chuang, H. H. Activity-dependent targeting of TRPV1 with a pore-permeating capsaicin analog. Proc. Natl Acad. Sci. USA 108, 8497–8502 (2011).
Story, G. M. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003).
Bautista, D. M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006).
Bessac, B. F. et al. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J. Clin. Invest. 118, 1899–1910 (2008).
Satoh, J. & Yamakage, M. Desflurane induces airway contraction mainly by activating transient receptor potential A1 of sensory C-fibers. J. Anesth. 23, 620–623 (2009).
Bessac, B. F. et al. Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J. 23, 1102–1114 (2009). This was the first demonstration that activation of TRPA1 is both necessary and sufficient to cause nocifensive reflexes in response to inhalation of a broadly reactive respiratory irritant.
Taylor-Clark, T. E., Kiros, F., Carr, M. J. & McAlexander, M. A. Transient receptor potential ankyrin 1 mediates toluene diisocyanate-evoked respiratory irritation. Am. J. Respir. Cell Mol. Biol. 40, 756–762 (2009).
Taylor-Clark, T. E. & Undem, B. J. Ozone activates airway nerves via the selective stimulation of TRPA1 ion channels. J. Physiol. 588, 423–433 (2010).
Cruz-Orengo, L. et al. Cutaneous nociception evoked by 15-δ PGJ2 via activation of ion channel TRPA1. Mol. Pain 4, 30 (2008).
Trevisani, M. et al. 4-hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc. Natl Acad. Sci. USA 104, 13519–13524 (2007).
Kwan, K. Y. et al. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50, 277–289 (2006).
McNamara, C. R. et al. TRPA1 mediates formalin-induced pain. Proc. Natl Acad. Sci. USA 104, 13525–13530 (2007).
Petrus, M. et al. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol. Pain 3, 40 (2007).
Eid, S. R. et al. HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity. Mol. Pain 4, 48 (2008).
Wei, H., Hamalainen, M. M., Saarnilehto, M., Koivisto, A. & Pertovaara, A. Attenuation of mechanical hypersensitivity by an antagonist of the TRPA1 ion channel in diabetic animals. Anesthesiology 111, 147–154 (2009).
Katsura, H. et al. Antisense knock down of TRPA1, but not TRPM8, alleviates cold hyperalgesia after spinal nerve ligation in rats. Exp. Neurol. 200, 112–123 (2006).
del Camino, D. et al. TRPA1 contributes to cold hypersensitivity. J. Neurosci. 30, 15165–15174 (2010).
da Costa, D. S. et al. The involvement of the transient receptor potential A1 (TRPA1) in the maintenance of mechanical and cold hyperalgesia in persistent inflammation. Pain 148, 431–437 (2010).
Chen, J. et al. Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain 152, 1165–1172 (2011).
McGaraughty, S. et al. TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats. Mol. Pain 6, 14 (2010). This was the first demonstration that a TRPA1 antagonist is capable of relieving pathological pain in animal models without altering cold sensation in naive animals.
Kerstein, P. C., del Camino, D., Moran, M. M. & Stucky, C. L. Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors. Mol. Pain 5, 19 (2009).
Kremeyer, B. et al. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 66, 671–680 (2010). This paper was the first to link the activity of a TRP channel to a pain syndrome in humans. It also suggested that potentiation of TRPA1 by cold temperatures is physiologically relevant, as cold is one of the triggers for pain episodes in patients suffering from pain syndromes.
Cheng, X. et al. TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation. Cell 141, 331–343 (2010).
Xu, H., Delling, M., Jun, J. C. & Clapham, D. E. Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nature Neurosci. 9, 628–635 (2006).
Gopinath, P. et al. Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain. BMC Womens Health 5, 2 (2005).
Facer, P. et al. Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMC Neurol. 7, 11 (2007). This was the first report of disease-related changes in the expression of TRPV1, TRPV3 and TRPV4 in painful disease states in humans.
Xiao, R. et al. Calcium plays a central role in the sensitization of TRPV3 channel to repetitive stimulations. J. Biol. Chem. 283, 6162–6174 (2008).
Khairatkar Joshi, N., Maharaj, N. & Thomas, A. The TRPV3 receptor as a pain target: a therapeutic promise or just some more new biology? Open Drug Discov. J. 2, 88–95 (2010).
Moqrich, A. et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307, 1468–1472 (2005).
Okazawa, M. et al. Noxious heat receptors present in cold-sensory cells in rats. Neurosci. Lett. 359, 33–36 (2004).
Dhaka, A. et al. TRPM8 is required for cold sensation in mice. Neuron 54, 371–378 (2007).
Bautista, D. M. et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448, 204–208 (2007).
Colburn, R. W. et al. Attenuated cold sensitivity in TRPM8 null mice. Neuron 54, 379–386 (2007).
Proudfoot, C. J. et al. Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr. Biol. 16, 1591–1605 (2006).
Parks, D. J. et al. Design and optimization of benzimidazole-containing transient receptor potential melastatin 8 (TRPM8) antagonists. J. Med. Chem. 54, 233–247 (2011).
Andersson, K. E., Gratzke, C. & Hedlund, P. The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder. BJU Int. 106, 1114–1127 (2010).
Avelino, A. & Cruz, F. TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications. Naunyn Schmiedebergs Arch. Pharmacol. 373, 287–299 (2006).
Everaerts, W. et al. Functional characterization of transient receptor potential channels in mouse urothelial cells. Am. J. Physiol. Renal Physiol. 298, F692–F701 (2010).
Birder, L. A. et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nature Neurosci. 5, 856–860 (2002).
MacDonald, R., Monga, M., Fink, H. A. & Wilt, T. J. Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: a systematic review of effectiveness and adverse effects. J. Spinal Cord Med. 31, 157–165 (2008).
Cruz, C. D. et al. Intrathecal delivery of resiniferatoxin (RTX) reduces detrusor overactivity and spinal expression of TRPV1 in spinal cord injured animals. Exp. Neurol. 214, 301–308 (2008).
Cruz, F. & Dinis, P. Resiniferatoxin and botulinum toxin type A for treatment of lower urinary tract symptoms. Neurourol. Urodyn. 26, 920–927 (2007).
Sculptoreanu, A., de Groat, W. C., Buffington, C. A. & Birder, L. A. Protein kinase C contributes to abnormal capsaicin responses in DRG neurons from cats with feline interstitial cystitis. Neurosci. Lett. 381, 42–46 (2005).
Charrua, A. et al. GRC-6211, a new oral specific TRPV1 antagonist, decreases bladder overactivity and noxious bladder input in cystitis animal models. J. Urol. 181, 379–386 (2009).
Gevaert, T. et al. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J. Clin. Invest. 117, 3453–3462 (2007).
Everaerts, W. et al. Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc. Natl Acad. Sci. USA 107, 19084–19089 (2010).
Mochizuki, T. et al. The TRPV4 cation channel mediates stretch-evoked Ca2+ influx and ATP release in primary urothelial cell cultures. J. Biol. Chem. 284, 21257–21264 (2009).
Thorneloe, K. S. et al. N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl} -3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: part I. J. Pharmacol. Exp. Ther. 326, 432–442 (2008).
Mukerji, G. et al. Cool and menthol receptor TRPM8 in human urinary bladder disorders and clinical correlations. BMC Urol. 6, 6 (2006).
Lashinger, E. S. et al. AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome. Am. J. Physiol. Renal Physiol. 295, F803–F810 (2008).
Paus, R., Schmelz, M., Biro, T. & Steinhoff, M. Frontiers in pruritus research: scratching the brain for more effective itch therapy. J. Clin. Invest. 116, 1174–1186 (2006).
Biro, T. et al. TRP channels as novel players in the pathogenesis and therapy of itch. Biochim. Biophys. Acta 1772, 1004–1021 (2007).
Bodo, E. et al. Vanilloid receptor-1 (VR1) is widely expressed on various epithelial and mesenchymal cell types of human skin. J. Invest. Dermatol. 123, 410–413 (2004).
Stander, S. et al. Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp. Dermatol. 13, 129–139 (2004).
Shim, W. S. et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J. Neurosci. 27, 2331–2337 (2007).
Weisshaar, E., Heyer, G., Forster, C. & Handwerker, H. O. Effect of topical capsaicin on the cutaneous reactions and itching to histamine in atopic eczema compared to healthy skin. Arch. Dermatol. Res. 290, 306–311 (1998).
Alenmyr, L., Hogestatt, E. D., Zygmunt, P. M. & Greiff, L. TRPV1-mediated itch in seasonal allergic rhinitis. Allergy 64, 807–810 (2009).
Wilson, S. R. et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nature Neurosci. 14, 595–602 (2011). This study showed that TRPA1 not only mediates pain and airway irritation but is also required for histamine-independent itch.
Carrillo, P. et al. Cutaneous wounds produced by capsaicin treatment of newborn rats are due to trophic disturbances. Neurotoxicol. Teratol. 20, 75–81 (1998).
Lagerstrom, M. C. et al. VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron 68, 529–542 (2010).
Liu, Y. et al. VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 68, 543–556 (2010).
Bodo, E. et al. A hot new twist to hair biology: involvement of vanilloid receptor-1 (VR1/TRPV1) signaling in human hair growth control. Am. J. Pathol. 166, 985–998 (2005). This study was the first to show that TRPV1 expressed on non-neuronal skin cells is involved in the regulation of cell growth.
Toth, B. I. et al. Endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential Vanilloid-1. J. Invest. Dermatol. 131, 1095–1104 (2011).
Denda, M., Sokabe, T., Fukumi-Tominaga, T. & Tominaga, M. Effects of skin surface temperature on epidermal permeability barrier homeostasis. J. Invest. Dermatol. 127, 654–659 (2007).
Lee, Y. M., Kim, Y. K. & Chung, J. H. Increased expression of TRPV1 channel in intrinsically aged and photoaged human skin in vivo. Exp. Dermatol. 18, 431–436 (2009).
Lee, Y. M. et al. A novel role for the TRPV1 channel in UV-induced matrix metalloproteinase (MMP)-1 expression in HaCaT cells. J. Cell Physiol. 219, 766–775 (2009).
Peier, A. M. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049 (2002).
Asakawa, M. et al. Association of a mutation in TRPV3 with defective hair growth in rodents. J. Invest. Dermatol. 126, 2664–2672 (2006).
Yoshioka, T. et al. Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice. J. Invest. Dermatol. 129, 714–722 (2009). These experiments demonstrated that a gain-of-function mutation in the Trpv3 gene results in severe dermatitis in mice; the TRPV3 protein is abundant in keratinocytes.
Borbiro, I., Geczy, T., Paus, R., Kovacs, L. & Biro, T. Activation of transient receptor potential vanilloid-3 (TRPV3) inhibits human hair growth. J. Invest. Dermatol. 128, S151 (2008).
Mazzone, S. B. & Undem, B. J. Cough sensors. V. Pharmacological modulation of cough sensors. Handb. Exp. Pharmacol. 187, 99–127 (2009).
Carr, M. J. & Lee, L. Y. Plasticity of peripheral mechanisms of cough. Respir. Physiol. Neurobiol. 152, 298–311 (2006).
Fujimura, M. et al. Prostanoids and cough response to capsaicin in asthma and chronic bronchitis. Eur. Respir. J. 8, 1499–1505 (1995).
Blom, H. M. et al. Intranasal capsaicin is efficacious in non-allergic, non-infectious perennial rhinitis. A placebo-controlled study. Clin. Exp. Allergy 27, 796–801 (1997).
Matta, J. A. et al. General anesthetics activate a nociceptive ion channel to enhance pain and inflammation. Proc. Natl Acad. Sci. USA 105, 8784–8789 (2008).
Andrè, E. et al. Cigarette smoke-induced neurogenic inflammation is mediated by α,β-unsaturated aldehydes and the TRPA1 receptor in rodents. J. Clin. Invest. 118, 2574–2582 (2008).
Birrell, M. A. et al. TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am. J. Respir. Crit. Care Med. 180, 1042–1047 (2009).
Talavera, K. et al. Nicotine activates the chemosensory cation channel TRPA1. Nature Neurosci. 12, 1293–1299 (2009).
Caceres, A. I. et al. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc. Natl Acad. Sci. USA 106, 9099–9104 (2009).
Nassini, R. et al. Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents. FASEB J. 24, 4904–4916 (2010).
Weissmann, N. et al. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc. Natl Acad. Sci. USA 103, 19093–19098 (2006).
Yu, Y. et al. A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation 119, 2313–2322 (2009).
White, T. A. et al. Role of transient receptor potential C3 in TNF-α-enhanced calcium influx in human airway myocytes. Am. J. Respir. Cell. Mol. Biol. 35, 243–251 (2006).
Xiao, J. H., Zheng, Y. M., Liao, B. & Wang, Y. X. Functional role of canonical transient receptor potential 1 and canonical transient receptor potential 3 in normal and asthmatic airway smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 43, 17–25 (2010).
Sel, S. et al. Loss of classical transient receptor potential 6 channel reduces allergic airway response. Clin. Exp. Allergy 38, 1548–1558 (2008).
Jia, Y. et al. Functional TRPV4 channels are expressed in human airway smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L272–L278 (2004).
Zhu, G. et al. Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease. Hum. Mol. Genet. 18, 2053–2062 (2009). This was the first study to suggest that TRPV4 can regulate lung function in humans.
Li, J. et al. TRPV4-mediated calcium-influx into human bronchial epithelia upon exposure to diesel exhaust particles. Environ. Health Perspect. 119, 784–793 (2011).
Jian, M. Y., King, J. A., Al-Mehdi, A. B., Liedtke, W. & Townsley, M. I. High vascular pressure-induced lung injury requires P450 epoxygenase-dependent activation of TRPV4. Am. J. Respir. Cell Mol. Biol. 38, 386–392 (2008).
Hamanaka, K. et al. TRPV4 initiates the acute calcium-dependent permeability increase during ventilator-induced lung injury in isolated mouse lungs. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L923–L932 (2007).
Willette, R. N. et al. Systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: part 2. J. Pharmacol. Exp. Ther. 326, 443–452 (2008).
Hamanaka, K. et al. TRPV4 channels augment macrophage activation and ventilator-induced lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 299, L353–L362 (2010).
Mizoguchi, F. et al. Transient receptor potential vanilloid 4 deficiency suppresses unloading-induced bone loss. J. Cell Physiol. 216, 47–53 (2008).
Masuyama, R. et al. TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. Cell. Metab. 8, 257–265 (2008).
Dai, J. et al. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J. Med. Genet. 47, 704–709 (2010).
Rock, M. J. et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nature Genet. 40, 999–1003 (2008).
Krakow, D. et al. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am. J. Hum. Genet. 84, 307–315 (2009).
Auer-Grumbach, M. et al. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nature Genet. 42, 160–164 (2010).
Landoure, G. et al. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nature Genet. 42, 170–174 (2010).
Feng, S. et al. Identification and functional characterization of an N-terminal oligomerization domain for polycystin-2. J. Biol. Chem. 283, 28471–28479 (2008).
Nauli, S. M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genet. 33, 129–137 (2003).
Sharif-Naeini, R. et al. Polycystin-1 and -2 dosage regulates pressure sensing. Cell 139, 587–596 (2009).
Winn, M. P. et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308, 1801–1804 (2005).
Moller, C. C. et al. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J. Am. Soc. Nephrol. 18, 29–36 (2007).
Reiser, J. et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nature Genet. 37, 739–744 (2005).
Wang, Y. et al. Activation of NFAT signaling in podocytes causes glomerulosclerosis. J. Am. Soc. Nephrol. 21, 1657–1666 (2010).
Chubanov, V. et al. Hypomagnesemia with secondary hypocalcemia due to a missense mutation in the putative pore-forming region of TRPM6. J. Biol. Chem. 282, 7656–7667 (2007).
Schlingmann, K. P. et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nature Genet. 31, 166–170 (2002).
Schlingmann, K. P. et al. Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia. J. Am. Soc. Nephrol. 16, 3061–3069 (2005).
Dong, X. P. et al. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455, 992–996 (2008).
Szallasi, A. & Di Marzo, V. New perspectives on enigmatic vanilloid receptors. Trends Neurosci. 23, 491–497 (2000).
Cavanaugh, D. et al. Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle. J. Neurosci. 31, 5067–5077 (2011). This careful study highlighted the challenges of determining the expression pattern for a target of interest, and the need to combine multiple approaches.
Marsch, R. et al. Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J. Neurosci. 27, 832–839 (2007).
Mezey, E. et al. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc. Natl Acad. Sci. USA 97, 3655–3660 (2000).
Kauer, J. A. & Gibson, H. E. Hot flash: TRPV channels in the brain. Trends Neurosci. 32, 215–224 (2009).
Grueter, B. A., Brasnjo, G. & Malenka, R. C. Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens. Nature Neurosci. 13, 1519–1525 (2010).
Jia, Y., Zhou, J., Tai, Y. & Wang, Y. TRPC channels promote cerebellar granule neuron survival. Nature Neurosci. 10, 559–567 (2007).
Hartmann, J. et al. TRPC3 channels are required for synaptic transmission and motor coordination. Neuron 59, 392–398 (2008).
Becker, E. B. et al. A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice. Proc. Natl Acad. Sci. USA 106, 6706–6711 (2009).
Riccio, A. et al. Essential role for TRPC5 in amygdala function and fear-related behavior. Cell 137, 761–772 (2009). This study was the first to implicate TRPC5 in anxiety. The neuronal recordings obtained in the study suggest that there is a potential link between TRPC5 and the CCK4 pathway.
Greka, A., Navarro, B., Oancea, E., Duggan, A. & Clapham, D. E. TRPC5 is a regulator of hippocampal neurite length and growth cone morphology. Nature Neurosci. 6, 837–845 (2003).
Miller, B. A. & Zhang, W. TRP channels as mediators of oxidative stress. Adv. Exp. Med. Biol. 704, 531–544 (2011).
Xu, C. et al. TRPM2 variants and bipolar disorder risk: confirmation in a family-based association study. Bipolar Disord. 11, 1–10 (2009).
Aarts, M. et al. A key role for TRPM7 channels in anoxic neuronal death. Cell 115, 863–877 (2003).
Lehen'kyi, V. & Prevarskaya, N. Oncogenic TRP channels. Adv. Exp. Med. Biol. 704, 929–945 (2011).
Tsavaler, L., Shapero, M. H., Morkowski, S. & Laus, R. Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res. 61, 3760–3769 (2001).
Thebault, S. et al. Novel role of cold/menthol-sensitive transient receptor potential melastatine family member 8 (TRPM8) in the activation of store-operated channels in LNCaP human prostate cancer epithelial cells. J. Biol. Chem. 280, 39423–39435 (2005).
Reading, S. A. & Brayden, J. E. Central role of TRPM4 channels in cerebral blood flow regulation. Stroke 38, 2322–2328 (2007).
Kruse, M. et al. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J. Clin. Invest. 119, 2737–2744 (2009).
Liu, H. et al. Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease. Circ. Cardiovasc. Genet. 3, 374–385 (2010).
Mathar, I. et al. Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice. J. Clin. Invest. 120, 3267–3279 (2010).
Onohara, N. et al. TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J. 25, 5305–5316 (2006).
Brixel, L. R. et al. TRPM5 regulates glucose-stimulated insulin secretion. Pflugers Arch. 460, 69–76 (2010).
Colsoul, B. et al. Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5−/− mice. Proc. Natl Acad. Sci. USA 107, 5208–5213 (2010). This study identified TRPM5 as a potential target for antidiabetic drugs.
Suri, A. & Szallasi, A. The emerging role of TRPV1 in diabetes and obesity. Trends Pharmacol. Sci. 29, 29–36 (2008).
Motter, A. L. & Ahern, G. P. TRPV1-null mice are protected from diet-induced obesity. FEBS Lett. 582, 2257–2262 (2008).
Biro, T. et al. Hair cycle control by vanilloid receptor-1 (TRPV1): evidence from TRPV1 knockout mice. J. Invest. Dermatol. 126, 1909–1912 (2006).
Toth, B. I. et al. Transient receptor potential vanilloid-1 signaling as a regulator of human sebocyte biology. J. Invest. Dermatol. 129, 329–339 (2009).
Beck, B. et al. TRPC channels determine human keratinocyte differentiation: new insight into basal cell carcinoma. Cell Calcium 43, 492–505 (2008).
Pani, B. et al. Up-regulation of transient receptor potential canonical 1 (TRPC1) following sarco(endo)plasmic reticulum Ca2+ ATPase 2 gene silencing promotes cell survival: a potential role for TRPC1 in Darier's disease. Mol. Biol. Cell 17, 4446–4458 (2006).
Atoyan, R., Shander, D. & Botchkareva, N. V. Non-neuronal expression of transient receptor potential type A1 (TRPA1) in human skin. J. Invest. Dermatol. 129, 2312–2315 (2009).
Lehen'kyi, V. et al. TRPV6 is a Ca2+ entry channel essential for Ca2+-induced differentiation of human keratinocytes. J. Biol. Chem. 282, 22582–22591 (2007).
McNeill, M. S. et al. Cell death of melanophores in zebrafish trpm7 mutant embryos depends on melanin synthesis. J. Invest. Dermatol. 127, 2020–2030 (2007).
Kiyonaka, S. et al. Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. Proc. Natl Acad. Sci. USA 106, 5400–5405 (2009).
Venkatachalam, K. et al. Motor deficit in a Drosophila model of mucolipidosis type IV due to defective clearance of apoptotic cells. Cell 135, 838–851 (2008).
Lambert, S. et al. Transient receptor potential melastatin 1 (TRPM1) is an ion-conducting plasma membrane channel inhibited by zinc ions. J. Biol. Chem. 286, 12221–12233 (2011).
Bellone, R. R. et al. Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus). Genetics 179, 1861–1870 (2008).
Audo, I. et al. TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness. Am. J. Hum. Genet. 85, 720–729 (2009).
Li, Z. et al. Recessive mutations of the gene TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness in humans. Am. J. Hum. Genet. 85, 711–719 (2009).
van Genderen, M. M. et al. Mutations in TRPM1 are a common cause of complete congenital stationary night blindness. Am. J. Hum. Genet. 85, 730–736 (2009).
Uchida, K. et al. Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice. Diabetes 60, 119–126 (2011).
Harteneck, C., Frenzel, H. & Kraft, R. N-(p-amylcinnamoyl)anthranilic acid (ACA): a phospholipase A(2) inhibitor and TRP channel blocker. Cardiovasc. Drug Rev. 25, 61–75 (2007).
Walder, R. Y. et al. Mice defective in Trpm6 show embryonic mortality and neural tube defects. Hum. Mol. Genet. 18, 4367–4375 (2009).
Jin, J. et al. Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis. Science 322, 756–760 (2008).
Hermosura, M. C. et al. A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders. Proc. Natl Acad. Sci. USA 102, 11510–11515 (2005).
Chen, H. C. et al. Blockade of TRPM7 channel activity and cell death by inhibitors of 5-lipoxygenase. PLoS ONE 5, e11161 (2010).
Higashi, Y., Kiuchi, T. & Furuta, K. Efficacy and safety profile of a topical methyl salicylate and menthol patch in adult patients with mild to moderate muscle strain: a randomized, double-blind, parallel-group, placebo-controlled, multicenter study. Clin. Ther. 32, 34–43 (2010).
Garcia-Gonzalez, M. A. et al. Pkd1 and Pkd2 are required for normal placental development. PLoS ONE 5, e12821 (2010).
Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517–524 (2003).
Scholz, J. & Clifford, J. W. Can we conquer pain? Nature Neurosci. 5, 1062–1067 (2002).
Acknowledgements
We would like to thank B. Nilius for reading the manuscript and providing useful comments, and M. Trevisani for his help in compiling the TRPV1 antagonist clinical trials database.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
Magdalene M. Moran works at Hydra Biosciences and has stock options in the company. Hydra Biosciences focuses on TRP channels and has programmes on some of the TRP channels that are discussed in the Review.
Michael Allen McAlexander is a full-time employee at GlaxoSmithKline.
Arpad Szallasi is a paid consultant to two small biotechnology companies with active TRP channel drug discovery programmes.
Tamás Bíró declares no competing financial interests.
Supplementary information
Supplementary information S1 (box)
Clinical trials with TRPV1 antagonists (PDF 279 kb)
Supplementary information S2 (table)
(PDF 420 kb)
Glossary
- 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.
- 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.
- 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.
- 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)
- 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.
- 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.
- 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.
Rights and permissions
About this article
Cite this article
Moran, M., McAlexander, M., Bíró, T. et al. Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 10, 601–620 (2011). https://doi.org/10.1038/nrd3456
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrd3456
This article is cited by
-
TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases
Signal Transduction and Targeted Therapy (2023)
-
Activation of TRPV1 receptor facilitates myelin repair following demyelination via the regulation of microglial function
Acta Pharmacologica Sinica (2023)
-
Gender-specific effects of capsiate supplementation on body weight and bone mineral density: a randomized, double-blind, placebo-controlled study in slightly overweight women
Journal of Endocrinological Investigation (2023)
-
TRPA1 participation in behavioral impairment induced by chronic corticosterone administration
Psychopharmacology (2023)
-
Advances in TRP channel drug discovery: from target validation to clinical studies
Nature Reviews Drug Discovery (2022)