1932

Abstract

The transient receptor potential (TRP) superfamily of channels comprises a diverse group of cation channels. Four TRP channel subunits coassemble to form functional homo- or heterotetramers that pass sodium, calcium, or both in the inward direction. Modulating TRP channel activity provides an important way to impact cellular function by regulating both membrane excitability and intracellular calcium levels. The import of these channels is underscored by the number of genetic diseases caused when they are mutated: Skeletal, skin, sensory, ocular, cardiac, and neuronal disturbances all arise from aberrant TRP function. Not surprisingly, there has been significant pharmaceutical interest in targeting these fascinating channels. Compounds that modulate TRP vanilloid 1 (TRPV1), TRPV3, TRPV4, TRP ankyrin 1 (TRPA1), and TRP melastatin 8 (TRPM8) have all entered clinical trials. The goal of this review is to familiarize the readers with the rationale behind the pursuit of these channels in drug discovery and the status of those efforts.

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2018-01-06
2024-06-18
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Literature Cited

  1. Cosens DJ, Manning A. 1.  1969. Abnormal electroretinogram from a Drosophila mutant. Nature 224:285–87 [Google Scholar]
  2. Huynh KW, Cohen MR, Jiang J, Samanta A, Lodowski DT. 2.  et al. 2016. Structure of the full-length TRPV2 channel by cryo-EM. Nat. Commun. 7:11130 [Google Scholar]
  3. Liao M, Cao E, Julius D, Cheng Y. 3.  2013. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504:107–12 [Google Scholar]
  4. Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D. 4.  2015. Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature 520:511–17 [Google Scholar]
  5. Shen PS, Yang X, DeCaen PG, Liu X, Bulkley D. 5.  et al. 2016. The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Cell 167:763–73.e11 [Google Scholar]
  6. Zubcevic L, Herzik MA Jr., Chung BC, Liu Z, Lander GC, Lee SY. 6.  2016. Cryo-electron microscopy structure of the TRPV2 ion channel. Nat. Struct. Mol. Biol. 23:180–86 [Google Scholar]
  7. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. 7.  1997. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–24 [Google Scholar]
  8. Prescott ED, Julius D. 8.  2003. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300:1284–88 [Google Scholar]
  9. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J. 9.  et al. 2000. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–13 [Google Scholar]
  10. Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT. 10.  et al. 2000. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405:183–87 [Google Scholar]
  11. Gavva NR, Treanor JJ, Garami A, Fang L, Surapaneni S. 11.  et al. 2008. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136:202–10 [Google Scholar]
  12. Krarup AL, Ny L, Astrand M, Bajor A, Hvid-Jensen F. 12.  et al. 2011. Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain. Aliment. Pharmacol. Ther. 33:1113–22 [Google Scholar]
  13. Eid SR. 13.  2011. Therapeutic targeting of TRP channels - the TR(i)P to pain relief. Curr. Top. Med. Chem. 11:2118–30 [Google Scholar]
  14. Chiche D, Brown W, Walker P. 14.  2016. NEO6860, a novel modality selective TRPV1 antagonist: results from a phase I, double-blind, placebo-controlled study in healthy subjects. J. Pain 17:S79 [Google Scholar]
  15. Jones VM, Moore KA, Peterson DM. 15.  2011. Capsaicin 8% topical patch (Qutenza)—a review of the evidence. J. Pain Palliat. Care Pharmacother. 25:32–41 [Google Scholar]
  16. 16. Centrexion Ther. 2016. Centrexion Therapeutics announces highly statistically significant topline results from Phase 2b study of CNTX-4975 in patients with knee osteoarthritis pain. News Release, Dec. 13. http://centrexion.com/wp-content/uploads/2016/12/CNTRX_12_13.pdf
  17. Szallasi A. 17.  1996. Vanilloid-sensitive neurons: a fundamental subdivision of the peripheral nervous system. J. Peripher. Nerv. Syst. 1:6–18 [Google Scholar]
  18. Chard PS, Bleakman D, Savidge JR, Miller RJ. 18.  1995. Capsaicin-induced neurotoxicity in cultured dorsal root ganglion neurons: involvement of calcium-activated proteases. Neuroscience 65:1099–108 [Google Scholar]
  19. Iadarola MJ, Gonnella GL. 19.  2013. Resiniferatoxin for pain treatment: an interventional approach to personalized pain medicine. Open Pain J 6:95–107 [Google Scholar]
  20. Brown DC, Agnello K, Iadarola MJ. 20.  2015. Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain. Pain 156:1018–24 [Google Scholar]
  21. McKemy DD, Neuhausser WM, Julius D. 21.  2002. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52–58 [Google Scholar]
  22. Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI. 22.  et al. 2007. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448:204–8 [Google Scholar]
  23. Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A. 23.  2007. TRPM8 is required for cold sensation in mice. Neuron 54:371–78 [Google Scholar]
  24. Colburn RW, Lubin ML, Stone DJ Jr., Wang Y. Lawrence D. 24.  et al. 2007. Attenuated cold sensitivity in TRPM8 null mice. Neuron 54:379–86 [Google Scholar]
  25. Dhaka A, Earley TJ, Watson J, Patapoutian A. 25.  2008. Visualizing cold spots: TRPM8-expressing sensory neurons and their projections. J. Neurosci. 28:566–75 [Google Scholar]
  26. Macpherson LJ, Xiao B, Kwan KY, Petrus MJ, Dubin AE. 26.  et al. 2007. An ion channel essential for sensing chemical damage. J. Neurosci. 27:11412–15 [Google Scholar]
  27. Macpherson LJ, Hwang SW, Miyamoto T, Dubin AE, Patapoutian A, Story GM. 27.  2006. More than cool: promiscuous relationships of menthol and other sensory compounds. Mol. Cell Neurosci. 32:335–43 [Google Scholar]
  28. Haeseler G, Maue D, Grosskreutz J, Bufler J, Nentwig B. 28.  et al. 2002. Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol. Eur. J. Anaesthesiol. 19:571–79 [Google Scholar]
  29. Swandulla D, Carbone E, Schäfer K, Lux HD. 29.  1987. Effect of menthol on two types of Ca currents in cultured sensory neurons of vertebrates. Pflüg. Arch. 409:52–59 [Google Scholar]
  30. Andrews MD, af Forselles K, Beaumont K, Galan SRG, Glossop PA. 30.  et al. 2015. Discovery of a selective TRPM8 antagonist with clinical efficacy in cold-related pain. ACS Med. Chem. Lett. 6:419–24 [Google Scholar]
  31. Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F. 31.  et al. 2010. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 66:671–80 [Google Scholar]
  32. Hinman A, Chuang HH, Bautista DM, Julius D. 32.  2006. TRP channel activation by reversible covalent modification. PNAS 103:19564–68 [Google Scholar]
  33. Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG. 33.  et al. 2007. Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445:541–45 [Google Scholar]
  34. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM. 34.  et al. 2004. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–65 [Google Scholar]
  35. Bautista DM, Movahed P, Hinman A, Axelsson HE, Sterner O. 35.  et al. 2005. Pungent products from garlic activate the sensory ion channel TRPA1. PNAS 102:12248–52 [Google Scholar]
  36. Macpherson LJ, Geierstanger BH, Viswanath V, Bandell M, Eid SR. 36.  et al. 2005. The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr. Biol. 15:929–34 [Google Scholar]
  37. Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR. 37.  et al. 2004. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849–57 [Google Scholar]
  38. McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL. 38.  et al. 2007. TRPA1 mediates formalin-induced pain. PNAS 104:13525–30 [Google Scholar]
  39. Bessac BF, Sivula M, von Hehn CA, Caceres AI, Escalera J, Jordt SE. 39.  2009. Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J 23:1102–14 [Google Scholar]
  40. Brone B, Peeters PJ, Marrannes R, Mercken M, Nuydens R. 40.  et al. 2008. Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor. Toxicol. Appl. Pharmacol. 231:150–56 [Google Scholar]
  41. Babes A, Sauer SK, Moparthi L, Kichko TI, Neacsu C. 41.  et al. 2016. Photosensitization in porphyrias and photodynamic therapy involves TRPA1 and TRPV1. J. Neurosci. 36:5264–78 [Google Scholar]
  42. Miyake T, Nakamura S, Zhao M, So K, Inoue K. 42.  et al. 2016. Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS. Nat. Commun. 7:12840 [Google Scholar]
  43. Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE. 43.  2008. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J. Clin. Investig. 118:1899–910 [Google Scholar]
  44. Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R. 44.  et al. 2007. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. PNAS 104:13519–24 [Google Scholar]
  45. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J. 45.  et al. 2003. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–29 [Google Scholar]
  46. del Camino D, Murphy S, Heiry M, Barrett LB, Earley TJ. 46.  et al. 2010. TRPA1 contributes to cold hypersensitivity. J. Neurosci. 30:15165–74 [Google Scholar]
  47. Doerner JF, Gisselmann G, Hatt H, Wetzel CH. 47.  2007. Transient receptor potential channel A1 is directly gated by calcium ions. J. Biol. Chem. 282:13180–89 [Google Scholar]
  48. Wang YY, Chang RB, Waters HN, McKemy DD, Liman ER. 48.  2008. The nociceptor ion channel TRPA1 is potentiated and inactivated by permeating calcium ions. J. Biol. Chem. 283:32691–703 [Google Scholar]
  49. de Oliveira C Garami A, Lehto SG, Pakai E, Tekus V. 49.  et al. 2014. Transient receptor potential channel ankyrin-1 is not a cold sensor for autonomic thermoregulation in rodents. J. Neurosci. 34:4445–52 [Google Scholar]
  50. Knowlton WM, Bifolck-Fisher A, Bautista DM, McKemy DD. 50.  2010. TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo. Pain 150:340–50 [Google Scholar]
  51. Karashima Y, Talavera K, Everaerts W, Janssens A, Kwan KY. 51.  et al. 2009. TRPA1 acts as a cold sensor in vitro and in vivo. PNAS 106:1273–78 [Google Scholar]
  52. da Costa DS, Meotti FC, Andrade EL, Leal PC, Motta EM, Calixto JB. 52.  2010. The involvement of the transient receptor potential A1 (TRPA1) in the maintenance of mechanical and cold hyperalgesia in persistent inflammation. Pain 148:431–37 [Google Scholar]
  53. Petrus M, Peier AM, Bandell M, Hwang SW, Huynh T. 53.  et al. 2007. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol. Pain 3:40 [Google Scholar]
  54. Chen J, Joshi SK, DiDomenico S, Perner RJ, Mikusa JP. 54.  et al. 2011. Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain 152:1165–72 [Google Scholar]
  55. Nassini R, Gees M, Harrison S, De Siena G Materazzi S. 55.  et al. 2011. Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation. Pain 152:1621–31 [Google Scholar]
  56. Trevisan G, Materazzi S, Fusi C, Altomare A, Aldini G. 56.  et al. 2013. Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade. Cancer Res 73:3120–31 [Google Scholar]
  57. Kerstein PC, del Camino D, Moran MM, Stucky CL. 57.  2009. Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors. Mol. Pain 5:19 [Google Scholar]
  58. Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS. 58.  et al. 2006. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50:277–89 [Google Scholar]
  59. Materazzi S, Fusi C, Benemei S, Pedretti P, Patacchini R. 59.  et al. 2012. TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflüg. Arch. 463:561–69 [Google Scholar]
  60. Moran MM, del Camino D, Hayward NJ, Curtis R, Murphy C. 60.  et al. 2011. TRPA1 antagonists reduce pain behaviors in a rat model of chemotherapy induced peripheral neuropathy Presented at Soc. Neurosci., Nov. 13, Washington, D.C. [Google Scholar]
  61. Wei H, Chapman H, Saarnilehto M, Kuokkanen K, Koivisto A, Pertovaara A. 61.  2010. Roles of cutaneous versus spinal TRPA1 channels in mechanical hypersensitivity in the diabetic or mustard oil-treated non-diabetic rat. Neuropharmacology 58:578–84 [Google Scholar]
  62. Wei H, Hamalainen MM, Saarnilehto M, Koivisto A, Pertovaara A. 62.  2009. Attenuation of mechanical hypersensitivity by an antagonist of the TRPA1 ion channel in diabetic animals. Anesthesiology 111:147–54 [Google Scholar]
  63. Koivisto A, Hukkanen M, Saarnilehto M, Chapman H, Kuokkanen K. 63.  et al. 2012. Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy. Pharmacol. Res. 65:149–58 [Google Scholar]
  64. Andersson DA, Filipovic MR, Gentry C, Eberhardt M, Vastani N. 64.  et al. 2015. Streptozotocin stimulates the ion channel TRPA1 directly: involvement of peroxynitrite. J. Biol. Chem. 290:15185–96 [Google Scholar]
  65. Eid SR, Crown ED, Moore EL, Liang HA, Choong KC. 65.  et al. 2008. HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity. Mol. Pain 4:48 [Google Scholar]
  66. Garrison SR, Stucky CL. 66.  2014. Contribution of transient receptor potential ankyrin 1 to chronic pain in aged mice with complete Freund's adjuvant–induced arthritis. Arthritis Rheumatol 66:2380–90 [Google Scholar]
  67. Rooney L, Vidal A, D'Souza AM, Devereux N, Masick B. 67.  et al. 2014. Discovery, optimization, and biological evaluation of 5-(2-(trifluoromethyl)phenyl)indazoles as a novel class of transient receptor potential A1 (TRPA1) antagonists. J. Med. Chem. 57:5129–40 [Google Scholar]
  68. Lehto SG, Weyer AD, Youngblood BD, Zhang M, Yin R. 68.  et al. 2016. Selective antagonism of TRPA1 produces limited efficacy in models of inflammatory- and neuropathic-induced mechanical hypersensitivity in rats. Mol. Pain 12: https://doi.org/10.1177/1744806916677761 [Crossref] [Google Scholar]
  69. Engel MA, Leffler A, Niedermirtl F, Babes A, Zimmermann K. 69.  et al. 2011. TRPA1 and substance P mediate colitis in mice. Gastroenterology 141:1346–58 [Google Scholar]
  70. Schwartz ES, La JH, Scheff NN, Davis BM, Albers KM, Gebhart GF. 70.  2013. TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis. J. Neurosci. 33:5603–11 [Google Scholar]
  71. Glenmark Pharmaceuticals. 71.  2014. Glenmark's TRPA1 antagonist ‘GRC 17536’ shows positive data in a proof of concept study News Release, Sept. 17. http://www.prnewswire.com/news-releases/glenmarks-trpa1-antagonist-grc-17536-shows-positive-data-in-a-proof-of-concept-study-275445961.html [Google Scholar]
  72. Tey HL, Wallengren J, Yosipovitch G. 72.  2013. Psychosomatic factors in pruritus. Clin. Dermatol. 31:31–40 [Google Scholar]
  73. Han L, Ma C, Liu Q, Weng HJ, Cui Y. 73.  et al. 2013. A subpopulation of nociceptors specifically linked to itch. Nat. Neurosci. 16:174–82 [Google Scholar]
  74. Shim WS, Tak MH, Lee MH, Kim M, Kim M. 74.  et al. 2007. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J. Neurosci. 27:2331–37 [Google Scholar]
  75. Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI. 75.  et al. 2009. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. PNAS 106:11330–35 [Google Scholar]
  76. Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN. 76.  et al. 2011. TRPA1 is required for histamine-independent, Mas-related G protein–coupled receptor–mediated itch. Nat. Neurosci. 14:595–602 [Google Scholar]
  77. Alemi F, Kwon E, Poole DP, Lieu T, Lyo V. 77.  et al. 2013. The TGR5 receptor mediates bile acid-induced itch and analgesia. J. Clin. Investig. 123:1513–30 [Google Scholar]
  78. Lieu T, Jayaweera G, Zhao P, Poole DP, Jensen D. 78.  et al. 2014. The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 147:1417–28 [Google Scholar]
  79. Morita T, McClain SP, Batia LM, Pellegrino M, Wilson SR. 79.  et al. 2015. HTR7 mediates serotonergic acute and chronic itch. Neuron 87:124–38 [Google Scholar]
  80. Liang J, Ji Q, Ji W. 80.  2011. Role of transient receptor potential ankyrin subfamily member 1 in pruritus induced by endothelin-1. Neurosci. Lett. 492:175–78 [Google Scholar]
  81. Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T. 81.  et al. 2014. A sensory neuron–expressed IL-31 receptor mediates T helper cell–dependent itch: involvement of TRPV1 and TRPA1. J. Allergy Clin. Immunol. 133:448–60 [Google Scholar]
  82. Wilson SR, Thé L, Batia LM, Beattie K, Katibah GE. 82.  et al. 2013. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155:285–95 [Google Scholar]
  83. Gauvreau GM, O'Byrne PM, Boulet LP, Wang Y, Cockcroft D. 83.  et al. 2014. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N. Engl. J. Med. 370:2102–10 [Google Scholar]
  84. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A. 84.  et al. 2016. Two Phase 3 trials of dupilumab versus placebo in atopic dermatitis. N. Engl. J. Med. 375:2335–48 [Google Scholar]
  85. Oh MH, Oh SY, Lu J, Lou H, Myers AC. 85.  et al. 2013. TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis. J. Immunol. 191:5371–82 [Google Scholar]
  86. Liu B, Escalera J, Balakrishna S, Fan L, Caceres AI. 86.  et al. 2013. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J 27:3549–63 [Google Scholar]
  87. Khalid S, Murdoch R, Newlands A, Smart K, Kelsall A. 87.  et al. 2014. Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial. J. Allergy Clin. Immunol. 134:56–62 [Google Scholar]
  88. Buday T, Brozmanova M, Biringerova Z, Gavliakova S, Poliacek I. 88.  et al. 2012. Modulation of cough response by sensory inputs from the nose - role of trigeminal TRPA1 versus TRPM8 channels. Cough 8:11 [Google Scholar]
  89. Birrell MA, Belvisi MG, Grace M, Sadofsky L, Faruqi S. 89.  et al. 2009. TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am. J. Respir. Crit. Care Med. 180:1042–47 [Google Scholar]
  90. Grace M, Birrell MA, Dubuis E, Maher SA, Belvisi MG. 90.  2012. Transient receptor potential channels mediate the tussive response to prostaglandin E2 and bradykinin. Thorax 67:891–900 [Google Scholar]
  91. Mukhopadhyay I, Kulkarni A, Aranake S, Karnik P, Shetty M. 91.  et al. 2014. Transient receptor potential ankyrin 1 receptor activation in vitro and in vivo by pro-tussive agents: GRC 17536 as a promising anti-tussive therapeutic. PLOS ONE 9:e97005 [Google Scholar]
  92. Trankner D, Hahne N, Sugino K, Hoon MA, Zuker C. 92.  2014. Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways. PNAS 111:11515–20 [Google Scholar]
  93. Talbot S, Abdulnour RE, Burkett PR, Lee S, Cronin SJ. 92a.  et al. 2015. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87:341–54 [Google Scholar]
  94. Caceres AI, Brackmann M, Elia MD, Bessac BF, del Camino D. 93.  et al. 2009. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. PNAS 106:9099–104 [Google Scholar]
  95. Nassini R, Pedretti P, Moretto N, Fusi C, Carnini C. 94.  et al. 2012. Transient receptor potential ankyrin 1 channel localized to non-neuronal airway cells promotes non-neurogenic inflammation. PLOS ONE 7:e42454 [Google Scholar]
  96. Buch TR, Schafer EA, Demmel MT, Boekhoff I, Thiermann H. 95.  et al. 2013. Functional expression of the transient receptor potential channel TRPA1, a sensor for toxic lung inhalants, in pulmonary epithelial cells. Chem. Biol. Interact. 206:462–71 [Google Scholar]
  97. Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ. 96.  et al. 2006. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124:1269–82 [Google Scholar]
  98. Deering-Rice CE, Romero EG, Shapiro D, Hughen RW, Light AR. 97.  et al. 2011. Electrophilic components of diesel exhaust particles (DEP) activate transient receptor potential ankyrin-1 (TRPA1): a probable mechanism of acute pulmonary toxicity for DEP. Chem. Res. Toxicol. 24:950–59 [Google Scholar]
  99. Fisk MZ, Steigerwald MD, Smoliga JM, Rundell KW. 98.  2010. Asthma in swimmers: a review of the current literature. Phys. Sportsmed 38:28–34 [Google Scholar]
  100. Mountjoy M, Fitch K, Boulet LP, Bougault V, van Mechelen W, Verhagen E. 99.  2015. Prevalence and characteristics of asthma in the aquatic disciplines. J. Allergy Clin. Immunol. 136:588–94 [Google Scholar]
  101. Agabiti N, Mallone S, Forastiere F, Corbo GM, Ferro S. 100.  et al. 1999. The impact of parental smoking on asthma and wheezing. Epidemiology 10:692–98 [Google Scholar]
  102. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM. 101.  et al. 2014. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 371:1198–207 [Google Scholar]
  103. Wenzel S, Castro M, Corren J, Maspero J, Wang L. 102.  et al. 2016. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 388:31–44 [Google Scholar]
  104. Raemdonck K, de Alba J, Birrell MA, Grace M, Maher SA. 103.  et al. 2012. A role for sensory nerves in the late asthmatic response. Thorax 67:19–25 [Google Scholar]
  105. Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS. 104.  et al. 2000. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103:525–35 [Google Scholar]
  106. Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD. 105.  2000. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat. Cell Biol. 2:695–702 [Google Scholar]
  107. Guler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M. 106.  2002. Heat-evoked activation of the ion channel, TRPV4. J. Neurosci. 22:6408–14 [Google Scholar]
  108. Watanabe H, Vriens J, Suh SH, Benham CD, Droogmans G, Nilius B. 107.  2002. Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. J. Biol. Chem. 277:47044–51 [Google Scholar]
  109. Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B. 108.  2003. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–38 [Google Scholar]
  110. Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P. 109.  et al. 2007. Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J. Physiol. 578:715–33 [Google Scholar]
  111. Lechner SG, Markworth S, Poole K, Smith ES, Lapatsina L. 110.  et al. 2011. The molecular and cellular identity of peripheral osmoreceptors. Neuron 69:332–44 [Google Scholar]
  112. Willette RN, Bao W, Nerurkar S, Yue TL, Doe CP. 111.  et al. 2008. Systemic activation of the transient receptor potential vanilloid subtype 4 channel causes endothelial failure and circulatory collapse: part 2. J. Pharmacol. Exp. Ther. 326:443–52 [Google Scholar]
  113. Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S. 112.  et al. 2012. An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci. Transl. Med. 4:159ra48 [Google Scholar]
  114. Hamanaka K, Jian MY, Weber DS, Alvarez DF, Townsley MI. 113.  et al. 2007. 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:L923–32 [Google Scholar]
  115. Hamanaka K, Jian MY, Townsley MI, King JA, Liedtke W. 114.  et al. 2010. TRPV4 channels augment macrophage activation and ventilator-induced lung injury. Am J. Physiol. Lung. Cell Mol. Physiol. 299:L353–62 [Google Scholar]
  116. Balakrishna S, Song W, Achanta S, Doran SF, Liu B. 115.  et al. 2014. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. Am J. Physiol. Lung. Cell Mol. Physiol. 307:L158–72 [Google Scholar]
  117. Dalsgaard T, Sonkusare SK, Teuscher C, Poynter ME, Nelson MT. 116.  2016. Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice. Sci. Rep. 6:33841 [Google Scholar]
  118. Auer-Grumbach M, Olschewski A, Papic L, Kremer H, McEntagart ME. 117.  et al. 2010. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat. Genet. 42:160–64 [Google Scholar]
  119. Deng HX, Klein CJ, Yan J, Shi Y, Wu Y. 118.  et al. 2010. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat. Genet. 42:165–69 [Google Scholar]
  120. Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC. 119.  et al. 2010. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat. Genet. 42:170–74 [Google Scholar]
  121. Rock MJ, Prenen J, Funari VA, Funari TL, Merriman B. 120.  et al. 2008. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat. Genet. 40:999–1003 [Google Scholar]
  122. Dai J, Cho TJ, Unger S, Lausch E, Nishimura G. 121.  et al. 2010. TRPV4-pathy, a novel channelopathy affecting diverse systems. J. Hum. Genet. 55:400–2 [Google Scholar]
  123. Cho TJ, Matsumoto K, Fano V, Dai J, Kim OH. 122.  et al. 2012. TRPV4-pathy manifesting both skeletal dysplasia and peripheral neuropathy: a report of three patients. Am. J. Med. Genet. A 158A:795–802 [Google Scholar]
  124. Fleming J, Quan D. 123.  2016. A case of congenital spinal muscular atrophy with pain due to a mutation in TRPV4. Neuromuscul. Disord. 26:841–43 [Google Scholar]
  125. Nilius B, Voets T. 124.  2013. The puzzle of TRPV4 channelopathies. EMBO Rep 14:152–63 [Google Scholar]
  126. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G. 125.  1999. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397:259–63 [Google Scholar]
  127. Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T. 126.  et al. 2005. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308:1801–4 [Google Scholar]
  128. Chiang ML, Hawkins EP, Berry PL, Barrish J, Hill LL. 127.  1988. Diagnostic and prognostic significance of glomerular epithelial cell vacuolization and podocyte effacement in children with minimal lesion nephrotic syndrome and focal segmental glomerulosclerosis: an ultrastructural study. Clin. Nephrol. 30:8–14 [Google Scholar]
  129. Yoshikawa N, Ito H, Akamatsu R, Hazikano H, Okada S, Matsuo T. 128.  1986. Glomerular podocyte vacuolation in focal segmental glomerulosclerosis. Arch. Pathol. Lab. Med. 110:394–98 [Google Scholar]
  130. Riehle M, Büscher AK, Gohlke BO, Kaßmann M, Kolatsi-Joannou M. 129.  et al. 2016. TRPC6 G757D loss-of-function mutation associates with FSGS. J. Am. Soc. Nephrol. 27:2771–83 [Google Scholar]
  131. Büscher AK, Konrad M, Nagel M, Witzke O, Kribben A. 130.  et al. 2012. Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients. Clin. Nephrol. 78:47–53 [Google Scholar]
  132. Hofstra JM, Lainez S, van Kuijk WH, Schoots J, Baltissen MP. 131.  et al. 2013. New TRPC6 gain-of-function mutation in a non-consanguineous Dutch family with late-onset focal segmental glomerulosclerosis. Nephrol. Dial. Transplant. 28:1830–38 [Google Scholar]
  133. Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM. 132.  et al. 2005. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat. Genet. 37:739–44 [Google Scholar]
  134. Zhu B, Chen N, Wang ZH, Pan XX, Ren H. 133.  et al. 2009. Identification and functional analysis of a novel TRPC6 mutation associated with late onset familial focal segmental glomerulosclerosis in Chinese patients. Mutat. Res. 664:84–90 [Google Scholar]
  135. Moller CC, Wei C, Altintas MM, Li J, Greka A. 134.  et al. 2007. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J. Am. Soc. Nephrol. 18:29–36 [Google Scholar]
  136. Wang L, Jirka G, Rosenberg PB, Buckley AF, Gomez JA. 135.  et al. 2015. Gq signaling causes glomerular injury by activating TRPC6. J. Clin. Investig. 125:1913–26 [Google Scholar]
  137. Maier T, Follmann M, Hessler G, Kleemann HW, Hachtel S. 136.  et al. 2015. Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol-sensitive TRPC cation channels. Br. J. Pharmacol. 172:3650–60 [Google Scholar]
  138. Washburn DG, Holt DA, Dodson J, McAtee JJ, Terrell LR. 137.  et al. 2013. The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore. Bioorg. Med. Chem. Lett. 23:4979–84 [Google Scholar]
  139. Igarashi P, Somlo S. 138.  2002. Genetics and pathogenesis of polycystic kidney disease. J. Am. Soc. Nephrol. 13:2384–98 [Google Scholar]
  140. 139. Eur. Polycystic Kidney Dis. Consort. 1994. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77:881–94 [Google Scholar]
  141. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B. 140.  et al. 1996. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272:1339–42 [Google Scholar]
  142. Qian F, Watnick TJ, Onuchic LF, Germino GG. 141.  1996. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87:979–87 [Google Scholar]
  143. Pei Y, Watnick T, He N, Wang K, Liang Y. 142.  et al. 1999. Somatic PKD2 mutations in individual kidney and liver cysts support a “two-hit” model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 10:1524–29 [Google Scholar]
  144. Takakura A, Contrino L, Beck AW, Zhou J. 143.  2008. Pkd1 inactivation induced in adulthood produces focal cystic disease. J. Am. Soc. Nephrol. 19:2351–63 [Google Scholar]
  145. Ong AC, Wheatley DN. 144.  2003. Polycystic kidney disease—the ciliary connection. Lancet 361:774–76 [Google Scholar]
  146. Delling M, DeCaen PG, Doerner JF, Febvay S, Clapham DE. 145.  2013. Primary cilia are specialized calcium signalling organelles. Nature 504:311–14 [Google Scholar]
  147. DeCaen PG, Delling M, Vien TN, Clapham DE. 146.  2013. Direct recording and molecular identification of the calcium channel of primary cilia. Nature 504:315–18 [Google Scholar]
  148. Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ. 147.  et al. 2002. A heat-sensitive TRP channel expressed in keratinocytes. Science 296:2046–49 [Google Scholar]
  149. Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA. 148.  et al. 2002. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature 418:181–86 [Google Scholar]
  150. Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P. 149.  et al. 2002. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418:186–90 [Google Scholar]
  151. Doerner JF, Hatt H, Ramsey IS. 150.  2011. Voltage- and temperature-dependent activation of TRPV3 channels is potentiated by receptor-mediated PI(4,5)P2 hydrolysis. J. Gen. Physiol. 137:271–88 [Google Scholar]
  152. Xu H, Delling M, Jun JC, Clapham DE. 151.  2006. Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nat. Neurosci. 9:628–35 [Google Scholar]
  153. Cheng X, Jin J, Hu L, Shen D, Dong XP. 152.  et al. 2010. TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation. Cell 141:331–43 [Google Scholar]
  154. Lai-Cheong JE, Sethuraman G, Ramam M, Stone K, Simpson MA, McGrath JA. 153.  2012. Recurrent heterozygous missense mutation, p.Gly573Ser, in the TRPV3 gene in an Indian boy with sporadic Olmsted syndrome. Br. J. Dermatol. 167:440–42 [Google Scholar]
  155. Lin Z, Chen Q, Lee M, Cao X, Zhang J. 154.  et al. 2012. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J. Hum. Genet. 90:558–64 [Google Scholar]
  156. Zhi YP, Liu J, Han JW, Huang YP, Gao ZQ. 155.  et al. 2016. Two familial cases of Olmsted-like syndrome with a G573V mutation of the TRPV3 gene. Clin. Exp. Dermatol. 41:510–13 [Google Scholar]
  157. He Y, Zeng K, Zhang X, Chen Q, Wu J. 156.  et al. 2015. A gain-of-function mutation in TRPV3 causes focal palmoplantar keratoderma in a Chinese family. J. Investig. Dermatol. 135:907–9 [Google Scholar]
  158. Yoshioka T, Imura K, Asakawa M, Suzuki M, Oshima I. 157.  et al. 2009. Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice. J. Investig. Dermatol. 129:714–22 [Google Scholar]
  159. Broad LM, Mogg AJ, Eberle E, Tolley M, Li DL, Knopp KL. 158.  2016. TRPV3 in drug development. Pharmaceuticals 9:55 [Google Scholar]
  160. 159. Hindu Bus. Line. 2011. Glenmark Pharma completes ‘GRC 15300’ Phase-I clinical trials News Release, July 25. http://www.thehindubusinessline.com/companies/glenmark-pharma-completes-grc-15300-phasei-clinical-trials/article2292593.ece [Google Scholar]
  161. Grubisha O, Mogg AJ, Sorge JL, Ball LJ, Sanger H. 160.  et al. 2014. Pharmacological profiling of the TRPV3 channel in recombinant and native assays. Br. J. Pharmacol. 171:2631–44 [Google Scholar]
  162. Bargal R, Avidan N, Ben-Asher E, Olender Z, Zeigler M. 161.  et al. 2000. Identification of the gene causing mucolipidosis type IV. Nat. Genet. 26:118–23 [Google Scholar]
  163. Wakabayashi K, Gustafson AM, Sidransky E, Goldin E. 162.  2011. Mucolipidosis type IV: an update. Mol. Genet. Metab. 104:206–13 [Google Scholar]
  164. Dong XP, Cheng X, Mills E, Delling M, Wang F. 163.  et al. 2008. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455:992–96 [Google Scholar]
  165. Shen D, Wang X, Li X, Zhang X, Yao Z. 164.  et al. 2012. Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat. Commun. 3:731 [Google Scholar]
  166. Venugopal B, Browning MF, Curcio-Morelli C, Varro A, Michaud N. 165.  et al. 2007. Neurologic, gastric, and opthalmologic pathologies in a murine model of mucolipidosis type IV. Am J. Hum. Genet. 81:1070–83 [Google Scholar]
  167. Dong XP, Wang X, Shen D, Chen S, Liu M. 166.  et al. 2009. Activating mutations of the TRPML1 channel revealed by proline-scanning mutagenesis. J. Biol. Chem. 284:32040–52 [Google Scholar]
  168. Becker EBE, Oliver PL, Glitsch MD, Banks GT, Achilli F. 167.  et al. 2009. A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice. PNAS 106:6706–11 [Google Scholar]
  169. Hartmann J, Dragicevic E, Adelsberger H, Henning HA, Sumser M. 168.  et al. 2008. TRPC3 channels are required for synaptic transmission and motor coordination. Neuron 59:392–98 [Google Scholar]
  170. Leuner K, Kazanski V, Müller M, Essin K, Henke B. 169.  et al. 2007. Hyperforin—a key constituent of St. John's wort specifically activates TRPC6 channels. FASEB J 21:4101–11 [Google Scholar]
  171. Sell TS, Belkacemi T, Flockerzi V, Beck A. 170.  2014. Protonophore properties of hyperforin are essential for its pharmacological activity. Sci. Rep. 4:7500 [Google Scholar]
  172. Mori Y, Takada N, Okada T, Wakamori M, Imoto K. 171.  et al. 1998. Differential distribution of TRP Ca2+ channel isoforms in mouse brain. NeuroReport 9:507–15 [Google Scholar]
  173. Okada T, Shimizu S, Wakamori M, Maeda A, Kurosaki T. 172.  et al. 1998. Molecular cloning and functional characterization of a novel receptor-activated TRP Ca2+ channel from mouse brain. J. Biol. Chem. 273:10279–87 [Google Scholar]
  174. Riccio A, Li Y, Moon J, Kim KS, Smith KS. 173.  et al. 2009. Essential role for TRPC5 in amygdala function and fear-related behavior. Cell 137:761–72 [Google Scholar]
  175. Riccio A, Li Y, Tsvetkov E, Gapon S, Yao GL. 174.  et al. 2014. Decreased anxiety-like behavior and Gαq/11-dependent responses in the amygdala of mice lacking TRPC4 channels. J. Neurosci. 34:3653–67 [Google Scholar]
  176. Yang LP, Jiang FJ, Wu GS, Deng K, Wen M. 175.  et al. 2015. Acute treatment with a novel TRPC4/C5 channel inhibitor produces antidepressant and anxiolytic-like effects in mice. PLOS ONE 10:e0136255 [Google Scholar]
  177. Oancea E, Wicks NL. 176.  2011. TRPM1: new trends for an old TRP. Adv. Exp. Med. Biol. 704:135–45 [Google Scholar]
  178. Daumy X, Amarouch MY, Lindenbaum P, Bonnaud S, Charpentier E. 177.  et al. 2016. Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I. Int. J. Cardiol. 207:349–58 [Google Scholar]
  179. Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H. 178.  et al. 2002. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat. Genet. 31:166–70 [Google Scholar]
  180. Walder RY, Landau D, Meyer P, Shalev H, Tsolia M. 179.  et al. 2002. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat. Genet. 31:171–74 [Google Scholar]
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