Hanyang Med Rev HMR Hanyang Medical Reviews 1738-429X Hanyang University School of Medicine 10.7599/hmr.2011.31.2.116 Review Article The Role of Transient Receptor Potential Channel in Pain Jung Seung Jun M.D. Ph.D. Department of Physiology, Hanyang University College of Medicine, Seoul, Korea. Corresponding author (eurijj@naver.com) 05 2011 31 05 2011 31 2 116 122 08 04 2011 06 05 2011 Copyright © 2011 Hanyang University School of Medicine 2011

Transient receptor potential (TRP) channels, a large family of receptor channel proteins, initially attracted researchers in the pain field as key molecules in nociception, but later they became known as more general transducer molecules for various physical stresses. In this review, I will discuss their roles in thermal and mechanical sensation, and then consider their contribution to physiological pain.

 Pain Transient receptor potential channels Thermo-sensor Mechano-sensor Transducer Cosens DJ Manning A Abnormal electroretinogram from a Drosophila mutant Nature 1969 224 285 287 Caterina MJ Schumacher MA Tominaga M Rosen TA Levine JD Julius D The capsaicin receptor: a heat-activated ion channel in the pain pathway Nature 1997 389 816 824 Caterina MJ Transient receptor potential ion channels as participants in thermosensation and thermoregulation Am J Physiol Regul Integr Comp Physiol 2007 292 R64 R76 Clapham DE TRP channels as cellular sensors Nature 2003 426 517 524 Patapoutian A Tate S Woolf CJ Transient receptor potential channels: targeting pain at the source Nat Rev Drug Discov 2009 8 55 68 Broad LM Mogg AJ Beattie RE Ogden AM Blanco MJ Bleakman D TRP channels as emerging targets for pain therapeutics Expert Opin Ther Targets 2009 13 69 81 Lázár J Gharat L Khairathkar-Joshi N Blumberg PM Szallasi A Screening TRPV1 antagonists for the treatment of pain: lessons learned over a decade Expert Opin Drug Discov 2009 4 159 180 Tominaga M Caterina MJ Malmberg AB Rosen TA Gilbert H Skinner K Raumann BE Basbaum AI Julius D The cloned capsaicin receptor integrates multiple pain-producing stimuli Neuron 1998 21 531 543 Chuang HH Neuhausser WM Julius D The super-cooling agent icilin reveals a mechanism of coincidence detection by a temperature-sensitive TRP channel Neuron 2004 43 859 869 Alexander SP Mathie A Peters JA Guide to Receptors and Channels (GRAC), 3rd edition Br J Pharmacol 2008 153 Suppl 2 S1 S209 Dhaka A Earley TJ Watson J Patapoutian A Visualizing cold spots: TRPM8-expressing sensory neurons and their projections J Neurosci 2008 28 566 575 Yang BH Piao ZG Kim YB Lee CH Lee JK Park K Kim JS Oh SB Activation of vanilloid receptor 1 (VR1) by eugenol J Dent Res 2003 82 781 785 Kashiba H Uchida Y Takeda D Nishigori A Ueda Y Kuribayashi K Ohshima M TRPV2-immunoreactive intrinsic neurons in the rat intestine Neurosci Lett 2004 366 193 196 Lewinter RD Skinner K Julius D Basbaum AI Immunoreactive TRPV-2 (VRL-1), a capsaicin receptor homolog, in the spinal cord of the rat J Comp Neurol 2004 470 400 408 Stokes AJ Wakano C Del Carmen KA Koblan-Huberson M Turner H Formation of a physiological complex between TRPV2 and RGA protein promotes cell surface expression of TRPV2 J Cell Biochem 2005 94 669 683 Wainwright A Rutter AR Seabrook GR Reilly K Oliver KR Discrete expression of TRPV2 within the hypothalamo-neurohypophysial system: Implications for regulatory activity within the hypothalamic-pituitary-adrenal axis J Comp Neurol 2004 474 24 42 Woodbury CJ Zwick M Wang S Lawson JJ Caterina MJ Koltzenburg M Albers KM Koerber HR Davis BM Nociceptors lacking TRPV1 and TRPV2 have normal heat responses J Neurosci 2004 24 6410 6415 Shimosato G Amaya F Ueda M Tanaka Y Decosterd I Tanaka M Peripheral inflammation induces up-regulation of TRPV2 expression in rat DRG Pain 2005 119 225 232 Levine JD Alessandri-Haber N TRP channels: targets for the relief of pain Biochim Biophys Acta 2007 1772 989 1003 Moqrich A Hwang SW Earley TJ Petrus MJ Murray AN Spencer KS Andahazy M Story GM Patapoutian A Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin Science 2005 307 1468 1472 Togashi K Hara Y Tominaga T Higashi T Konishi Y Mori Y Tominaga M TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion EMBO J 2006 25 1804 1815 Talavera K Yasumatsu K Voets T Droogmans G Shigemura N Ninomiya Y Margolskee RF Nilius B Heat activation of TRPM5 underlies thermal sensitivity of sweet taste Nature 2005 438 1022 1025 Morin C Bushnell MC Temporal and qualitative properties of cold pain and heat pain: a psychophysical study Pain 1998 74 67 73 Foulkes T Wood JN Mechanisms of cold pain Channels (Austin) 2007 1 154 160 McKemy DD Neuhausser WM Julius D Identification of a cold receptor reveals a general role for TRP channels in thermosensation Nature 2002 416 52 58 Hensel H Zotterman Y The effect of menthol on the thermoreceptors Acta Physiol Scand 1951 24 27 34 Reid G Babes A Pluteanu F A cold- and menthol-activated current in rat dorsal root ganglion neurones: properties and role in cold transduction J Physiol 2002 545 595 614 Reid G Flonta ML Ion channels activated by cold and menthol in cultured rat dorsal root ganglion neurones Neurosci Lett 2002 324 164 168 Peier AM Moqrich A Hergarden AC Reeve AJ Andersson DA Story GM Earley TJ Dragoni I McIntyre P Bevan S Patapoutian A A TRP channel that senses cold stimuli and menthol Cell 2002 108 705 715 Tominaga M Caterina MJ Thermosensation and pain J Neurobiol 2004 61 3 12 Bautista DM Siemens J Glazer JM Tsuruda PR Basbaum AI Stucky CL Jordt SE Julius D The menthol receptor TRPM8 is the principal detector of environmental cold Nature 2007 448 204 208 Dhaka A Murray AN Mathur J Earley TJ Petrus MJ Patapoutian A TRPM8 is required for cold sensation in mice Neuron 2007 54 371 378 Dhaka A Viswanath V Patapoutian A Trp ion channels and temperature sensation Annu Rev Neurosci 2006 9 135 161 McKemy DD How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation Mol Pain 2005 1 16 Reid G ThermoTRP channels and cold sensing: what are they really up to? Pflugers Arch 2005 451 250 263 Story GM Peier AM Reeve AJ Eid SR Mosbacher J Hricik TR Earley TJ Hergarden AC Andersson DA Hwang SW McIntyre P Jegla T Bevan S Patapoutian A ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures Cell 2003 112 819 829 Hinman A Chuang HH Bautista DM Julius D TRP channel activation by reversible covalent modification Proc Natl Acad Sci U S A 2006 103 19564 19568 Macpherson LJ Dubin AE Evans MJ Marr F Schultz PG Cravatt BF Patapoutian A Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines Nature 2007 445 541 545 Fujita F Uchida K Moriyama T Shima A Shibasaki K Inada H Sokabe T Tominaga M Intracellular alkalization causes pain sensation through activation of TRPA1 in mice J Clin Invest 2008 118 4049 4057 Karashima Y Damann N Prenen J Talavera K Segal A Voets T Nilius B Bimodal action of menthol on the transient receptor potential channel TRPA1 J Neurosci 2007 27 9874 9884 Birder LA Kanai AJ de Groat WC Kiss S Nealen ML Burke NE Dineley KE Watkins S Reynolds IJ Caterina MJ Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells Proc Natl Acad Sci U S A 2001 98 13396 13401 Birder LA Nakamura Y Kiss S Nealen ML Barrick S Kanai AJ Wang E Ruiz G De Groat WC Apodaca G Watkins S Caterina MJ Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1 Nat Neurosci 2002 5 856 860 Jones RC 3rd Xu L Gebhart GF The mechanosensitivity of mouse colon afferent fibers and their sensitization by inflammatory mediators require transient receptor potential vanilloid 1 and acid-sensing ion channel 3 J Neurosci 2005 25 10981 10989 Miranda A Nordstrom E Mannem A Smith C Banerjee B Sengupta JN The role of transient receptor potential vanilloid 1 in mechanical and chemical visceral hyperalgesia following experimental colitis Neuroscience 2007 148 1021 1032 Cavanaugh DJ Lee H Lo L Shields SD Zylka MJ Basbaum AI Anderson DJ Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli Proc Natl Acad Sci U S A 2009 106 9075 9080 Brierley SM Page AJ Hughes PA Adam B Liebregts T Cooper NJ Holtmann G Liedtke W Blackshaw LA Selective role for TRPV4 ion channels in visceral sensory pathways Gastroenterology 2008 134 2059 2069 Grant AD Cottrell GS Amadesi S Trevisani M Nicoletti P Materazzi S Altier C Cenac N Zamponi GW Bautista-Cruz F Lopez CB Joseph EK Levine JD Liedtke W Vanner S Vergnolle N Geppetti P Bunnett NW Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice J Physiol 2007 578 715 733 Corey DP Garcia-Anoveros J Holt JR Kwan KY Lin SY Vollrath MA Amalfitano A Cheung EL Derfler BH Duggan A Geleoc GS Gray PA Hoffman MP Rehm HL Tamasauskas D Zhang DS TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells Nature 2004 432 723 730 Kwan KY Allchorne AJ Vollrath MA Christensen AP Zhang DS Woolf CJ Corey DP TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction Neuron 2006 50 277 289 Bautista DM Jordt SE Nikai T Tsuruda PR Read AJ Poblete J Yamoah EN Basbaum AI Julius D TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents Cell 2006 124 1269 1282 Christensen AP Corey DP TRP channels in mechanosensation: direct or indirect activation? Nat Rev Neurosci 2007 8 510 521 Guharay F Sachs F Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle J Physiol 1984 352 685 701 Beech DJ Muraki K Flemming R Non-selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP J Physiol 2004 559 685 706 Welsh DG Morielli AD Nelson MT Brayden JE Transient receptor potential channels regulate myogenic tone of resistance arteries Circ Res 2002 90 248 250 Spassova MA Hewavitharana T Xu W Soboloff J Gill DL A common mechanism underlies stretch activation and receptor activation of TRPC6 channels Proc Natl Acad Sci U S A 2006 103 16586 16591 Siemens J Zhou S Piskorowski R Nikai T Lumpkin EA Basbaum AI King D Julius D Spider toxins activate the capsaicin receptor to produce inflammatory pain Nature 2006 444 208 212 Yoshida T Inoue R Morii T Takahashi N Yamamoto S Hara Y Tominaga M Shimizu S Sato Y Mori Y Nitric oxide activates TRP channels by cysteine S-nitrosylation Nat Chem Biol 2006 2 596 607

Temperature thresholds, chemical agonists, and tissue distribution of six temperature-sensitive TRP channels. NADA, N-arachidonoyl-dopamine; 2-APB, 2-aminoethoxydiphenyl borate; DPBA, diphenylboronic anhydride; 4α-PDD, 4α-phorbol 12,13-didecanoate; PMA, phorbol 12-myristate 13-acetate; PtdIns (4,5)P2, phosphatidylinositol 4,5-bisphosphate; HNE, 4-hydroxynonenal; THC, tetrahydrocannabinol.30