Comprehensive Physiology Wiley Online Library

Molecular Mechanism of TRP Channels

Full Article on Wiley Online Library



Abstract

Transient receptor potential (TRP) channels are cellular sensors for a wide spectrum of physical and chemical stimuli. They are involved in the formation of sight, hearing, touch, smell, taste, temperature, and pain sensation. TRP channels also play fundamental roles in cell signaling and allow the host cell to respond to benign or harmful environmental changes. As TRP channel activation is controlled by very diverse processes and, in many cases, exhibits complex polymodal properties, understanding how each TRP channel responds to its unique forms of activation energy is both crucial and challenging. The past two decades witnessed significant advances in understanding the molecular mechanisms that underlie TRP channels activation. This review focuses on our current understanding of the molecular determinants for TRP channel activation. © 2013 American Physiological Society. Compr Physiol 3:221‐242, 2013.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

Transient receptor potential (TRP) channel subfamilies. The subunit topology is shown with highlights of specific functional domains. Subunits known to coassemble are indicated by lines.

Figure 2. Figure 2.

Electron microscopy (EM) structures of transient receptor potential (TRP) channels. (A) Cryo‐EM structures of TRPV1. Blue lines indicate the position of the cell membrane. (B) The crystal structures of Kv2.1 transmembrane domains (PDB 2A79) and TRPV1 ankyrin‐like repeat domains (PDB 2PNN) docked into the TRPV1 cryo‐EM structure. (C) Cryo‐EM structure of Shaker potassium channel. Adapted, with permission, from references (). Scale bar for A and C, 10 nm.

Figure 3. Figure 3.

(A) Crystal structure of the TRPV2 ankyrin‐like repeat domain. (B) Comparison between TRPV2 ankyrin‐like repeat domain and the repeats 16‐21 of ankyrin (PDB 1N11). (A) and (B) are Adapted, with permission, from reference (). (C) Crystal structures of the coiled‐coil domain of TRPM7 (left), TRPP2 (middle), and CNGA1 (right). Adapted, with permission, from references (), respectively.

Figure 4. Figure 4.

(A) schematic drawing of the voltage‐dependent gating of the Kv channel (left) and CLC‐0 channel (right). The red + and − signs indicate positive charged amino acids and chloride ion, respectively. For the Kv channel, charges carried by arginine and lysine residues in the fourth transmembrane segment, S4, serve as the primary gating charges. Changes in transmembrane voltage drive the movement of S4, which is coupled to the opening of the activation gate. For the CLC‐0 channel, the permeant ion Cl in the pore carries the gating charge. (B) Voltage‐dependent gating of TRPV1 and Kv channels.

Figure 5. Figure 5.

Temperature‐dependent activation of thermo TRP channels and CLC‐0 channel. The PopenT (top panel) and ΔGT (bottom panel) relationships for each channel are predicted from the measured values for enthalpic and entropic changes. Horizontal and vertical dotted lines indicate the zero ΔG level and the half‐activation temperature, respectively. Red and green traces represent the predicted PopenT and ΔGT relationships of TRPV1 when the enthalpic change is decreased or increased by 5%, respectively. The ΔGT relationship of heat‐sensitive channels has a negative slope; an increase in temperature causes a decrease in ΔG and a shift of the closed‐to‐open equilibrium toward the open state. In contrast, the ΔGT relationship of cold‐sensitive channels has a positive slope. CLC‐0 has a “normal” fast gating process and a highly temperature‐sensitive common gating process. Adapted, with permission, from reference ().

Figure 6. Figure 6.

(Left panel) At the cellular level, heat and capsaicin share the same target (TRPV1) for activating sensory neurons, which elicits the sensation of heat or pain. (Right panel) At the molecular level, heat and capsaicin work through distinct activation pathways.

Figure 7. Figure 7.

(A) The molecular structure of vanillin, TRPV1 activator capsaicin, capsazepine (TRPV1 antagonist), and resiniferatoxin (TRPV1 agonist). (B) Dose‐response relationship for TRPV1 homomeric channel and TRPV1/TRPV3 heteromeric channel. (C) Representative single‐channel traces from TRPV1 homomeric channel (top) and TRPV1/TRPV3 heteromeric channel (bottom) in response to 10 μmol/L capsaicin. Panels B and C are Adapted, with permission, from reference ().

Figure 8. Figure 8.

The molecular structure of the TRPM8 activator menthol, icilin, and eucalyptol.

Figure 9. Figure 9.

(A) A topology plot of TRPV1 subunit showing the major pH sites E600 and E648, and other pH sites. (B) (Left panel) A structural model of the mouse TRPV1 channel showing the location of E601 (equivalent to E600 of the rat TRPV1 channel; shown in space‐filling mode). (Right panel) Potential interaction between E601 and N626.



Figure 1.

Transient receptor potential (TRP) channel subfamilies. The subunit topology is shown with highlights of specific functional domains. Subunits known to coassemble are indicated by lines.



Figure 2.

Electron microscopy (EM) structures of transient receptor potential (TRP) channels. (A) Cryo‐EM structures of TRPV1. Blue lines indicate the position of the cell membrane. (B) The crystal structures of Kv2.1 transmembrane domains (PDB 2A79) and TRPV1 ankyrin‐like repeat domains (PDB 2PNN) docked into the TRPV1 cryo‐EM structure. (C) Cryo‐EM structure of Shaker potassium channel. Adapted, with permission, from references (). Scale bar for A and C, 10 nm.



Figure 3.

(A) Crystal structure of the TRPV2 ankyrin‐like repeat domain. (B) Comparison between TRPV2 ankyrin‐like repeat domain and the repeats 16‐21 of ankyrin (PDB 1N11). (A) and (B) are Adapted, with permission, from reference (). (C) Crystal structures of the coiled‐coil domain of TRPM7 (left), TRPP2 (middle), and CNGA1 (right). Adapted, with permission, from references (), respectively.



Figure 4.

(A) schematic drawing of the voltage‐dependent gating of the Kv channel (left) and CLC‐0 channel (right). The red + and − signs indicate positive charged amino acids and chloride ion, respectively. For the Kv channel, charges carried by arginine and lysine residues in the fourth transmembrane segment, S4, serve as the primary gating charges. Changes in transmembrane voltage drive the movement of S4, which is coupled to the opening of the activation gate. For the CLC‐0 channel, the permeant ion Cl in the pore carries the gating charge. (B) Voltage‐dependent gating of TRPV1 and Kv channels.



Figure 5.

Temperature‐dependent activation of thermo TRP channels and CLC‐0 channel. The PopenT (top panel) and ΔGT (bottom panel) relationships for each channel are predicted from the measured values for enthalpic and entropic changes. Horizontal and vertical dotted lines indicate the zero ΔG level and the half‐activation temperature, respectively. Red and green traces represent the predicted PopenT and ΔGT relationships of TRPV1 when the enthalpic change is decreased or increased by 5%, respectively. The ΔGT relationship of heat‐sensitive channels has a negative slope; an increase in temperature causes a decrease in ΔG and a shift of the closed‐to‐open equilibrium toward the open state. In contrast, the ΔGT relationship of cold‐sensitive channels has a positive slope. CLC‐0 has a “normal” fast gating process and a highly temperature‐sensitive common gating process. Adapted, with permission, from reference ().



Figure 6.

(Left panel) At the cellular level, heat and capsaicin share the same target (TRPV1) for activating sensory neurons, which elicits the sensation of heat or pain. (Right panel) At the molecular level, heat and capsaicin work through distinct activation pathways.



Figure 7.

(A) The molecular structure of vanillin, TRPV1 activator capsaicin, capsazepine (TRPV1 antagonist), and resiniferatoxin (TRPV1 agonist). (B) Dose‐response relationship for TRPV1 homomeric channel and TRPV1/TRPV3 heteromeric channel. (C) Representative single‐channel traces from TRPV1 homomeric channel (top) and TRPV1/TRPV3 heteromeric channel (bottom) in response to 10 μmol/L capsaicin. Panels B and C are Adapted, with permission, from reference ().



Figure 8.

The molecular structure of the TRPM8 activator menthol, icilin, and eucalyptol.



Figure 9.

(A) A topology plot of TRPV1 subunit showing the major pH sites E600 and E648, and other pH sites. (B) (Left panel) A structural model of the mouse TRPV1 channel showing the location of E601 (equivalent to E600 of the rat TRPV1 channel; shown in space‐filling mode). (Right panel) Potential interaction between E601 and N626.

 1. Alessandri‐Haber N, Dina OA, Chen X, Levine JD. TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. J Neurosci 29: 6217‐6228, 2009.
 2. Aneiros E, Cao L, Papakosta M, Stevens E, Phillips S, Grimm C. The biophysical and molecular basis of TRPV1 proton gating. EMBO J 30: 994‐1002, 2011.
 3. Arniges M, Fernandez‐Fernandez JM, Albrecht N, Schaefer M, Valverde MA. Human TRPV4 channel splice variants revealed a key role of ankyrin domains in multimerization and trafficking. J Biol Chem 281: 1580‐1586, 2006.
 4. Bai CX, Giamarchi A, Rodat‐Despoix L, Padilla F, Downs T, Tsiokas L, Delmas P. Formation of a new receptor‐operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits. EMBO Rep 9: 472‐479, 2008.
 5. Bandell M, Dubin AE, Petrus MJ, Orth A, Mathur J, Hwang SW, Patapoutian A. High‐throughput random mutagenesis screen reveals TRPM8 residues specifically required for activation by menthol. Nat Neurosci 9: 493‐500, 2006.
 6. Baumann TK, Martenson ME. Extracellular protons both increase the activity and reduce the conductance of capsaicin‐ gated channels. J Neurosci 20: RC80, 2000.
 7. Bezanilla F. How membrane proteins sense voltage. Nat Rev Mol Cell Biol 9: 323‐332, 2008.
 8. Birnbaumer L, Zhu X, Jiang M, Boulay G, Peyton M, Vannier B, Brown D, Platano D, Sadeghi H, Stefani E, Birnbaumer M. On the molecular basis and regulation of cellular capacitative calcium entry: Roles for Trp proteins. Proc Natl Acad Sci U S A 93: 15195‐15202, 1996.
 9. Blount P, Sukharev S, Kung C. A mechanosensitive channel protein and its gene in E. coli. Gravit Space Biol Bull 10: 43‐47, 1997.
 10. Boron WF. Acid‐base physiology. In: Boron WF, Boulpaep EL, editors. Medical Physiology, Philadelphia: Elsevier Saunders, 2005, pp. 633‐653.
 11. Brauchi S, Orio P, Latorre R. Clues to understanding cold sensation: Thermodynamics and electrophysiological analysis of the cold receptor TRPM8. Proc Natl Acad Sci U S A 101: 15494‐15499, 2004.
 12. Brauchi S, Orta G, Salazar M, Rosenmann E, Latorre R. A hot‐sensing cold receptor: C‐terminal domain determines thermosensation in transient receptor potential channels. J Neurosci 26: 4835‐4840, 2006.
 13. 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 389: 816‐824, 1997.
 14. Cavanaugh DJ, Chesler AT, Jackson AC, Sigal YM, Yamanaka H, Grant R, O'Donnell D, Nicoll RA, Shah NM, Julius D, Basbaum AI. Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. J Neurosci 31: 5067‐5077, 2011.
 15. Chang Q, Gyftogianni E, van de Graaf SF, Hoefs S, Weidema FA, Bindels RJ, Hoenderop JG. Molecular determinants in TRPV5 channel assembly. J Biol Chem 279: 54304‐54311, 2004.
 16. Cheng W, Sun C, Zheng J. Heteromerization of TRP channel subunits: Extending functional diversity. Protein Cell 1: 802‐810, 2010.
 17. Cheng W, Yang F, Liu S, Colton CK, Wang C, Cui Y, Cao X, Zhu MX, Sun C, Wang KW, Zheng J. Heteromeric heat‐sensitive TRP channels exhibit distinct temperature and chemical response. J Biol Chem 287: 7279‐7288, 2012.
 18. Cheng W, Yang F, Takanishi CL, Zheng J. Thermosensitive TRPV channel subunits coassemble into heteromeric channels with intermediate conductance and gating properties. J Gen Physiol 129: 191‐207, 2007.
 19. Chevesich J, Kreuz AJ, Montell C. Requirement for the PDZ domain protein, INAD, for localization of the TRP store‐operated channel to a signaling complex. Neuron 18: 95‐105, 1997.
 20. Chubanov V, Mederos y Schnitzler M, Waring J, Plank A, Gudermann T. Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes. Naunyn Schmiedebergs Arch Pharmacol 371: 334‐341, 2005.
 21. Chubanov V, Waldegger S, Mederos y Schnitzler M, Vitzthum H, Sassen MC, Seyberth HW, Konrad M, Gudermann T. Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proc Natl Acad Sci U S A 101: 2894‐2899, 2004.
 22. Ciura S, Bourque CW. Transient receptor potential vanilloid 1 is required for intrinsic osmoreception in organum vasculosum lamina terminalis neurons and for normal thirst responses to systemic hyperosmolality. J Neurosci 26: 9069‐9075, 2006.
 23. Clapham DE. TRP channels as cellular sensors. Nature 426: 517‐524, 2003.
 24. Clapham DE, Miller C. A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc Natl Acad Sci U S A 108: 19492‐19497, 2011.
 25. Clapham DE, Runnels LW, Strubing C. The TRP ion channel family. Nat Rev Neurosci 2: 387‐396, 2001.
 26. Cordero‐Morales JF, Gracheva EO, Julius D. Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli. Proc Natl Acad Sci U S A 108: E1184‐E1191, 2011.
 27. Cosens DJ, Manning A. Abnormal electroretinogram from a Drosophila mutant. Nature 224: 285‐287, 1969.
 28. Cui Y, Yang F, Cao X, Yarov‐Yarovoy V, Wang KW, Zheng J. Selective disruption of high‐sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations. J Gen Physiol 139: 273‐283, 2012.
 29. Curcio‐Morelli C, Zhang P, Venugopal B, Charles FA, Browning MF, Cantiello HF, Slaugenhaupt SA. Functional multimerization of mucolipin channel proteins. J Cell Physiol 222: 328‐335, 2010.
 30. Cvetkov TL, Huynh KW, Cohen MR, Moiseenkova‐Bell VY. Molecular architecture and subunit organization of TRPA1 channel revealed by electron microscopy. J Biol Chem 286: 38168‐38176, 2011.
 31. Dhaka A, Uzzell V, Dubin AE, Mathur J, Petrus M, Bandell M, Patapoutian A. TRPV1 is activated by both acidic and basic pH. J Neurosci 29: 153‐158, 2009.
 32. Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H. The type IV mucolipidosis‐associated protein TRPML1 is an endolysosomal iron release channel. Nature 455: 992‐996, 2008.
 33. Dong XP, Wang X, Xu H. TRP channels of intracellular membranes. J Neurochem 113: 313‐328, 2010.
 34. Du J, Xie J, Yue L. Modulation of TRPM2 by acidic pH and the underlying mechanisms for pH sensitivity. J Gen Physiol 134: 471‐488, 2009.
 35. Erickson MG, Alseikhan BA, Peterson BZ, Yue DT. Preassociation of calmodulin with voltage‐gated Ca(2+) channels revealed by FRET in single living cells. Neuron 31: 973‐985, 2001.
 36. Erler I, Hirnet D, Wissenbach U, Flockerzi V, Niemeyer BA. Ca2+‐selective transient receptor potential V channel architecture and function require a specific ankyrin repeat. J Biol Chem 279: 34456‐34463, 2004.
 37. Fan HC, Zhang X, McNaughton PA. Activation of the TRPV4 ion channel is enhanced by phosphorylation. J Biol Chem 284: 27884‐27891, 2009.
 38. Fernandez‐Ballester G, Ferrer‐Montiel A. Molecular modeling of the full‐length human TRPV1 channel in closed and desensitized states. J Membr Biol 223: 161‐172, 2008.
 39. 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, 118: 4049‐4057, 2008.
 40. Fujiwara Y, Minor DL, Jr. X‐ray crystal structure of a TRPM assembly domain reveals an antiparallel four‐stranded coiled‐coil. J Mol Biol 383: 854‐870, 2008.
 41. Gao X, Wu L, O'Neil RG. Temperature‐modulated diversity of TRPV4 channel gating: Activation by physical stresses and phorbol ester derivatives through protein kinase C‐dependent and ‐independent pathways. J Biol Chem 278: 27129‐27137, 2003.
 42. Garcia‐Sanz N, Fernandez‐Carvajal A, Morenilla‐Palao C, Planells‐Cases R, Fajardo‐Sanchez E, Fernandez‐Ballester G, Ferrer‐Montiel A. Identification of a tetramerization domain in the C terminus of the vanilloid receptor. J Neurosci 24: 5307‐5314, 2004.
 43. Gavva NR, Klionsky L, Qu Y, Shi L, Tamir R, Edenson S, Zhang TJ, Viswanadhan VN, Toth A, Pearce LV, Vanderah TW, Porreca F, Blumberg PM, Lile J, Sun Y, Wild K, Louis JC, Treanor JJ. Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem 279: 20283‐20295, 2004.
 44. Gavva NR, Treanor JJ, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, Jang GR, Kesslak JP, Ni L, Norman MH, Palluconi G, Rose MJ, Salfi M, Tan E, Romanovsky AA, Banfield C, Davar G. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136: 202‐210, 2008.
 45. Goel M, Sinkins WG, Schilling WP. Selective association of TRPC channel subunits in rat brain synaptosomes. J Biol Chem 277: 48303‐48310, 2002.
 46. Gordon‐Shaag A, Zagotta WN, Gordon SE. Mechanism of Ca(2+)‐dependent desensitization in TRP channels. Channels (Austin) 2: 125‐129, 2008.
 47. Gracheva EO, Ingolia NT, Kelly YM, Cordero‐Morales JF, Hollopeter G, Chesler AT, Sanchez EE, Perez JC, Weissman JS, Julius D. Molecular basis of infrared detection by snakes. Nature 464: 1006‐1011, 2010.
 48. Grandl J, Hu H, Bandell M, Bursulaya B, Schmidt M, Petrus M, Patapoutian A. Pore region of TRPV3 ion channel is specifically required for heat activation. Nat Neurosci 11: 1007‐1013, 2008.
 49. Grandl J, Kim SE, Uzzell V, Bursulaya B, Petrus M, Bandell M, Patapoutian A. Temperature‐induced opening of TRPV1 ion channel is stabilized by the pore domain. Nat Neurosci 13: 708‐714, 2010.
 50. Grigoryan G, Keating AE. Structural specificity in coiled‐coil interactions. Curr Opin Struct Biol 18: 477‐483, 2008.
 51. Gudermann T, Hofmann T, Mederos y Schnitzler M, Dietrich A. Activation, subunit composition and physiological relevance of DAG‐sensitive TRPC proteins. Novartis Found Symp 258: 103‐118; discussion 118‐122, 155‐109, 263‐106, 2004.
 52. Hardie RC, Minke B. The trp gene is essential for a light‐activated Ca2+ channel in Drosophila photoreceptors. Neuron 8: 643‐651, 1992.
 53. Hellwig N, Albrecht N, Harteneck C, Schultz G, Schaefer M. Homo‐ and heteromeric assembly of TRPV channel subunits. J Cell Sci 118: 917‐928, 2005.
 54. Henrich M, Buckler KJ. Acid‐evoked Ca2+ signalling in rat sensory neurones: Effects of anoxia and aglycaemia. Pflugers Arch 459: 159‐181, 2009.
 55. Hille B. Ion Channels of Excitable Membranes, Sunderland, Massachusetts: Sinauer Associates, Inc., 2001.
 56. Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ. Homo‐ and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J 22: 776‐785, 2003.
 57. Hofmann T, Chubanov V, Gudermann T, Montell C. TRPM5 is a voltage‐modulated and Ca(2+)‐activated monovalent selective cation channel. Curr Biol 13: 1153‐1158, 2003.
 58. Hofmann T, Schaefer M, Schultz G, Gudermann T. Subunit composition of mammalian transient receptor potential channels in living cells. Proc Natl Acad Sci U S A 99: 7461‐7466, 2002.
 59. Holzer P. Acid‐sensitive ion channels and receptors. Handb Exp Pharmacol (Suppl 194): 283‐332, 2009.
 60. Hoover DB. Effects of capsaicin on release of substance P‐like immunoreactivity and physiological parameters in isolated perfused guinea‐pig heart. Eur J Pharmacol 141: 489‐492, 1987.
 61. Horrigan FT, Aldrich RW. Allosteric voltage gating of potassium channels II. Mslo channel gating charge movement in the absence of Ca(2+). J Gen Physiol 114: 305‐336, 1999.
 62. Howard RJ, Clark KA, Holton JM, Minor DL, Jr. Structural insight into KCNQ (Kv7) channel assembly and channelopathy. Neuron 53: 663‐675, 2007.
 63. Hu CP, Xiao L, Deng HW, Li YJ. The cardioprotection of rutaecarpine is mediated by endogenous calcitonin related‐gene peptide through activation of vanilloid receptors in guinea‐pig hearts. Planta Med 68: 705‐709, 2002.
 64. Huang SM, Li X, Yu Y, Wang J, Caterina MJ. TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation. Mol Pain 7: 37, 2011.
 65. Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, Oh U. Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin‐like substances. Proc Natl Acad Sci U S A 97: 6155‐6160, 2000.
 66. Inada H, Kawabata F, Ishimaru Y, Fushiki T, Matsunami H, Tominaga M. Off‐response property of an acid‐activated cation channel complex PKD1L3‐PKD2L1. EMBO Rep 9: 690‐697, 2008.
 67. Inoue R, Jensen LJ, Jian Z, Shi J, Hai L, Lurie AI, Henriksen FH, Salomonsson M, Morita H, Kawarabayashi Y, Mori M, Mori Y, Ito Y. Synergistic activation of vascular TRPC6 channel by receptor and mechanical stimulation via phospholipase C/diacylglycerol and phospholipase A2/omega‐hydroxylase/20‐HETE pathways. Circ Res 104: 1399‐1409, 2009.
 68. Iwata Y, Katanosaka Y, Arai Y, Komamura K, Miyatake K, Shigekawa M. A novel mechanism of myocyte degeneration involving the Ca2+‐permeable growth factor‐regulated channel. J Cell Biol 161: 957‐967, 2003.
 69. Jahnel R, Dreger M, Gillen C, Bender O, Kurreck J, Hucho F. Biochemical characterization of the vanilloid receptor 1 expressed in a dorsal root ganglia derived cell line. Eur J Biochem 268: 5489‐5496, 2001.
 70. Jiang J, Li M, Yue L. Potentiation of TRPM7 inward currents by protons. J Gen Physiol 126: 137‐150, 2005.
 71. Jiang LH. Subunit interaction in channel assembly and functional regulation of transient receptor potential melastatin (TRPM) channels. Biochem Soc Trans 35: 86‐88, 2007.
 72. Jin X, Touhey J, Gaudet R. Structure of the N‐terminal ankyrin repeat domain of the TRPV2 ion channel. J Biol Chem 281: 25006‐25010, 2006.
 73. Jordt SE, Julius D. Molecular basis for species‐specific sensitivity to “hot” chili peppers. Cell 108: 421‐430, 2002.
 74. Jordt SE, Tominaga M, Julius D. Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci U S A 97: 8134‐8139, 2000.
 75. Jung J, Lee SY, Hwang SW, Cho H, Shin J, Kang YS, Kim S, Oh U. Agonist recognition sites in the cytosolic tails of vanilloid receptor 1. J Biol Chem 277: 44448‐44454, 2002.
 76. Kang D, Choe C, Kim D. Thermosensitivity of the two‐pore domain K+ channels TREK‐2 and TRAAK. J Physiol 564: 103‐116, 2005.
 77. Kanzaki M, Zhang YQ, Mashima H, Li L, Shibata H, Kojima I. Translocation of a calcium‐permeable cation channel induced by insulin‐like growth factor‐I. Nat Cell Biol 1: 165‐170, 1999.
 78. Kedei N, Szabo T, Lile JD, Treanor JJ, Olah Z, Iadarola MJ, Blumberg PM. Analysis of the native quaternary structure of vanilloid receptor 1. J Biol Chem 276: 28613‐28619, 2001.
 79. Kim MJ, Jeon JP, Kim HJ, Kim BJ, Lee YM, Choe H, Jeon JH, Kim SJ, So I. Molecular determinant of sensing extracellular pH in classical transient receptor potential channel 5. Biochem Biophys Res Commun 365: 239‐245, 2008.
 80. Kinoshita‐Kawada M, Tang J, Xiao R, Kaneko S, Foskett JK, Zhu MX. Inhibition of TRPC5 channels by Ca2+‐binding protein 1 in Xenopus oocytes. Pflugers Arch 450: 345‐354, 2005.
 81. Kloda A, Petrov E, Meyer GR, Nguyen T, Hurst AC, Hool L, Martinac B. Mechanosensitive channel of large conductance. Int J Biochem Cell Biol 40: 164‐169, 2008.
 82. Kobori T, Smith GD, Sandford R, Edwardson JM. The transient receptor potential channels TRPP2 and TRPC1 form a heterotetramer with a 2:2 stoichiometry and an alternating subunit arrangement. J Biol Chem 284: 35507‐35513, 2009.
 83. Kottgen M, Buchholz B, Garcia‐Gonzalez MA, Kotsis F, Fu X, Doerken M, Boehlke C, Steffl D, Tauber R, Wegierski T, Nitschke R, Suzuki M, Kramer‐Zucker A, Germino GG, Watnick T, Prenen J, Nilius B, Kuehn EW, Walz G. TRPP2 and TRPV4 form a polymodal sensory channel complex. J Cell Biol 182: 437‐447, 2008.
 84. Kozak JA, Matsushita M, Nairn AC, Cahalan MD. Charge screening by internal pH and polyvalent cations as a mechanism for activation, inhibition, and rundown of TRPM7/MIC channels. J Gen Physiol 126: 499‐514, 2005.
 85. Kuzhikandathil EV, Wang H, Szabo T, Morozova N, Blumberg PM, Oxford GS. Functional analysis of capsaicin receptor (vanilloid receptor subtype 1) multimerization and agonist responsiveness using a dominant negative mutation. J Neurosci 21: 8697‐8706, 2001.
 86. Lambers TT, Weidema AF, Nilius B, Hoenderop JG, Bindels RJ. Regulation of the mouse epithelial Ca2(+) channel TRPV6 by the Ca(2+)‐sensor calmodulin. J Biol Chem 279: 28855‐28861, 2004.
 87. Latorre R, Brauchi S, Orta G, Zaelzer C, Vargas G. ThermoTRP channels as modular proteins with allosteric gating. Cell Calcium 42: 427‐438, 2007.
 88. Li M, Du J, Jiang J, Ratzan W, Su LT, Runnels LW, Yue L. Molecular determinants of Mg2+ and Ca2+ permeability and pH sensitivity in TRPM6 and TRPM7. J Biol Chem 282: 25817‐25830, 2007.
 89. Li M, Jiang J, Yue L. Functional characterization of homo‐ and heteromeric channel kinases TRPM6 and TRPM7. J Gen Physiol 127: 525‐537, 2006.
 90. Liapi A, Wood JN. Extensive co‐localization and heteromultimer formation of the vanilloid receptor‐like protein TRPV2 and the capsaicin receptor TRPV1 in the adult rat cerebral cortex. Eur J Neurosci 22: 825‐834, 2005.
 91. Liedtke W, Choe Y, Marti‐Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S. Vanilloid receptor‐related osmotically activated channel (VR‐OAC), a candidate vertebrate osmoreceptor. Cell 103: 525‐535, 2000.
 92. Lishko PV, Procko E, Jin X, Phelps CB, Gaudet R. The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity. Neuron 54: 905‐918, 2007.
 93. Liu D, Zhang Z, Liman ER. Extracellular acid block and acid‐enhanced inactivation of the Ca2+‐activated cation channel TRPM5 involve residues in the S3‐S4 and S5‐S6 extracellular domains. J Biol Chem 280: 20691‐20699, 2005.
 94. Liu M, Chen TY, Ahamed B, Li J, Yau KW. Calcium‐calmodulin modulation of the olfactory cyclic nucleotide‐gated cation channel. Science 266: 1348‐1354, 1994.
 95. Liu X, Bandyopadhyay BC, Singh BB, Groschner K, Ambudkar IS. Molecular analysis of a store‐operated and 2‐acetyl‐sn‐glycerol‐sensitive non‐selective cation channel. Heteromeric assembly of TRPC1‐TRPC3. J Biol Chem 280: 21600‐21606, 2005.
 96. Long SB, Campbell EB, Mackinnon R. Crystal structure of a mammalian voltage‐dependent Shaker family K+ channel. Science 309: 897‐903, 2005.
 97. Ludtke SJ, Baker ML, Chen DH, Song JL, Chuang DT, Chiu W. De novo backbone trace of GroEL from single particle electron cryomicroscopy. Structure 16: 441‐448, 2008.
 98. MacKinnon R. Potassium channels. FEBS Lett 555: 62‐65, 2003.
 99. Malinowska B, Kwolek G, Gothert M. Anandamide and methanandamide induce both vanilloid VR1‐ and cannabinoid CB1 receptor‐mediated changes in heart rate and blood pressure in anaesthetized rats. Naunyn Schmiedebergs Arch Pharmacol 364: 562‐569, 2001.
 100. Manzini S, Perretti F, De Benedetti L, Pradelles P, Maggi CA, Geppetti P. A comparison of bradykinin‐ and capsaicin‐induced myocardial and coronary effects in isolated perfused heart of guinea‐pig: Involvement of substance P and calcitonin gene‐related peptide release. Br J Pharmacol 97: 303‐312, 1989.
 101. Maroto R, Raso A, Wood TG, Kurosky A, Martinac B, Hamill OP. TRPC1 forms the stretch‐activated cation channel in vertebrate cells. Nat Cell Biol 7: 179‐185, 2005.
 102. Maruyama Y, Ogura T, Mio K, Kiyonaka S, Kato K, Mori Y, Sato C. Three‐dimensional reconstruction using transmission electron microscopy reveals a swollen, bell‐shaped structure of transient receptor potential melastatin type 2 cation channel. J Biol Chem 282: 36961‐36970, 2007.
 103. Matta JA, Ahern GP. Voltage is a partial activator of rat thermosensitive TRP channels. J Physiol 585: 469‐482, 2007.
 104. McCleverty CJ, Koesema E, Patapoutian A, Lesley SA, Kreusch A. Crystal structure of the human TRPV2 channel ankyrin repeat domain. Protein Sci 15: 2201‐2206, 2006.
 105. McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416: 52‐58, 2002.
 106. Mio K, Ogura T, Hara Y, Mori Y, Sato C. The non‐selective cation‐permeable channel TRPC3 is a tetrahedron with a cap on the large cytoplasmic end. Biochem Biophys Res Commun 333: 768‐777, 2005.
 107. Mio K, Ogura T, Kiyonaka S, Hiroaki Y, Tanimura Y, Fujiyoshi Y, Mori Y, Sato C. The TRPC3 channel has a large internal chamber surrounded by signal sensing antennas. J Mol Biol 367: 373‐383, 2007.
 108. Miyazawa A, Fujiyoshi Y, Unwin N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423: 949‐955, 2003.
 109. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272: 1339‐1342, 1996.
 110. Moiseenkova‐Bell VY, Stanciu LA, Serysheva, II, Tobe BJ, Wensel TG. Structure of TRPV1 channel revealed by electron cryomicroscopy. Proc Natl Acad Sci U S A 105: 7451‐7455, 2008.
 111. Montell C, Rubin GM. Molecular characterization of the Drosophila trp locus: A putative integral membrane protein required for phototransduction. Neuron 2: 1313‐1323, 1989.
 112. Morita H, Honda A, Inoue R, Ito Y, Abe K, Nelson MT, Brayden JE. Membrane stretch‐induced activation of a TRPM4‐like nonselective cation channel in cerebral artery myocytes. J Pharmacol Sci 103: 417‐426, 2007.
 113. Mosavi LK, Cammett TJ, Desrosiers DC, Peng ZY. The ankyrin repeat as molecular architecture for protein recognition. Protein Sci 13: 1435‐1448, 2004.
 114. Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, Shigekawa M, Imaizumi Y. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ Res 93: 829‐838, 2003.
 115. Myers BR, Bohlen CJ, Julius D. A yeast genetic screen reveals a critical role for the pore helix domain in TRP channel gating. Neuron 58: 362‐373, 2008.
 116. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33: 129‐137, 2003.
 117. Nault MA, Vincent SG, Fisher JT. Mechanisms of capsaicin‐ and lactic acid‐induced bronchoconstriction in the newborn dog. J Physiol 515(Pt 2): 567‐578, 1999.
 118. Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C. Competitive regulation of CaT‐like‐mediated Ca2+ entry by protein kinase C and calmodulin. Proc Natl Acad Sci U S A 98: 3600‐3605, 2001.
 119. Nilius B, Prenen J, Droogmans G, Voets T, Vennekens R, Freichel M, Wissenbach U, Flockerzi V. Voltage dependence of the Ca2+‐activated cation channel TRPM4. J Biol Chem 278: 30813‐30820, 2003.
 120. Nilius B, Prenen J, Tang J, Wang C, Owsianik G, Janssens A, Voets T, Zhu MX. Regulation of the Ca2+ sensitivity of the nonselective cation channel TRPM4. J Biol Chem 280: 6423‐6433, 2005.
 121. Numata T, Okada Y. Proton conductivity through the human TRPM7 channel and its molecular determinants. J Biol Chem 283: 15097‐15103, 2008.
 122. Numata T, Shimizu T, Okada Y. Direct mechano‐stress sensitivity of TRPM7 channel. Cell Physiol Biochem 19: 1‐8, 2007.
 123. Numata T, Shimizu T, Okada Y. TRPM7 is a stretch‐ and swelling‐activated cation channel involved in volume regulation in human epithelial cells. Am J Physiol Cell Physiol 292: C460‐C467, 2007.
 124. Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M. Structural determinant of TRPV1 desensitization interacts with calmodulin. Proc Natl Acad Sci U S A 100: 8002‐8006, 2003.
 125. Oancea E, Wolfe JT, Clapham DE. Functional TRPM7 channels accumulate at the plasma membrane in response to fluid flow. Circ Res 98: 245‐253, 2006.
 126. Ordaz B, Tang J, Xiao R, Salgado A, Sampieri A, Zhu MX, Vaca L. Calmodulin and calcium interplay in the modulation of TRPC5 channel activity. Identification of a novel C‐terminal domain for calcium/calmodulin‐mediated facilitation. J Biol Chem 280: 30788‐30796, 2005.
 127. Oroszi G, Szilvassy Z, Nemeth J, Ferdinandy P, Szolcsanyi J, Tosaki A. Interaction between capsaicin and nitrate tolerance in isolated guinea‐pig heart. Eur J Pharmacol 368: R1‐R3, 1999.
 128. Papakosta M, Dalle C, Haythornthwaite A, Cao L, Stevens EB, Burgess G, Russell R, Cox PJ, Phillips SC, Grimm C. The chimeric approach reveals that differences in the TRPV1 pore domain determine species‐specific sensitivity to block of heat activation. J Biol Chem 286: 39663‐39672, 2011.
 129. Pedersen SF, Owsianik G, Nilius B. TRP channels: An overview. Cell Calcium 38: 233‐252, 2005.
 130. 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 108: 705‐715, 2002.
 131. Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P, Bevan S, Patapoutian A. A heat‐sensitive TRP channel expressed in keratinocytes. Science 296: 2046‐2049, 2002.
 132. Peng H, Lewandrowski U, Muller B, Sickmann A, Walz G, Wegierski T. Identification of a Protein Kinase C‐dependent phosphorylation site involved in sensitization of TRPV4 channel. Biochem Biophys Res Commun 391: 1721‐1725, 2010.
 133. Peterson BZ, DeMaria CD, Adelman JP, Yue DT. Calmodulin is the Ca2+ sensor for Ca2+‐dependent inactivation of L‐type calcium channels. Neuron 22: 549‐558, 1999.
 134. Phelps CB, Huang RJ, Lishko PV, Wang RR, Gaudet R. Structural analyses of the ankyrin repeat domain of TRPV6 and related TRPV ion channels. Biochemistry 47: 2476‐2484, 2008.
 135. Phelps CB, Wang RR, Choo SS, Gaudet R. Differential regulation of TRPV1, TRPV3, and TRPV4 sensitivity through a conserved binding site on the ankyrin repeat domain. J Biol Chem 285: 731‐740, 2010.
 136. Phillips AM, Bull A, Kelly LE. Identification of a Drosophila gene encoding a calmodulin‐binding protein with homology to the trp phototransduction gene. Neuron 8: 631‐642, 1992.
 137. Plant TD, Schaefer M. TRPC4 and TRPC5: Receptor‐operated Ca2+‐permeable nonselective cation channels. Cell Calcium 33: 441‐450, 2003.
 138. Plant TD, Schaefer M. Receptor‐operated cation channels formed by TRPC4 and TRPC5. Naunyn Schmiedebergs Arch Pharmacol 371: 266‐276, 2005.
 139. Poteser M, Graziani A, Rosker C, Eder P, Derler I, Kahr H, Zhu MX, Romanin C, Groschner K. TRPC3 and TRPC4 associate to form a redox‐sensitive cation channel. Evidence for expression of native TRPC3‐TRPC4 heteromeric channels in endothelial cells. J Biol Chem 281: 13588‐13595, 2006.
 140. Pusch M, Ludewig U, Jentsch TJ. Temperature dependence of fast and slow gating relaxations of ClC‐0 chloride channels. J Gen Physiol 109: 105‐116, 1997.
 141. Qin F, Auerbach A, Sachs F. Maximum likelihood estimation of aggregated Markov processes. Proc Biol Sci 264: 375‐383, 1997.
 142. Ramsey IS, Delling M, Clapham DE. An introduction to TRP channels. Annu Rev Physiol 68: 619‐647, 2006.
 143. Ramsey IS, Moran MM, Chong JA, Clapham DE. A voltage‐gated proton‐selective channel lacking the pore domain. Nature 440: 1213‐1216, 2006.
 144. Rang WQ, Du YH, Hu CP, Ye F, Xu KP, Peng J, Deng HW, Li YJ. Protective effects of evodiamine on myocardial ischemia‐reperfusion injury in rats. Planta Med 70: 1140‐1143, 2004.
 145. Rhoads AR, Friedberg F. Sequence motifs for calmodulin recognition. FASEB J 11: 331‐340, 1997.
 146. Rosenbaum T, Gordon‐Shaag A, Munari M, Gordon SE. Ca2+/calmodulin modulates TRPV1 activation by capsaicin. J Gen Physiol 123: 53‐62, 2004.
 147. Rutter AR, Ma QP, Leveridge M, Bonnert TP. Heteromerization and colocalization of TrpV1 and TrpV2 in mammalian cell lines and rat dorsal root ganglia. Neuroreport 16: 1735‐1739, 2005.
 148. Ryu S, Liu B, Qin F. Low pH potentiates both capsaicin binding and channel gating of VR1 receptors. J Gen Physiol 122: 45‐61, 2003.
 149. Ryu S, Liu B, Yao J, Fu Q, Qin F. Uncoupling proton activation of vanilloid receptor TRPV1. J Neurosci 27: 12797‐12807, 2007.
 150. Sachs F. Stretch‐activated ion channels: What are they? Physiology (Bethesda) 25: 50‐56, 2010.
 151. Sachs F, Sokabe M. Stretch‐activated ion channels and membrane mechanics. Neurosci Res Suppl 12: S1‐S4, 1990.
 152. Salas MM, Hargreaves KM, Akopian AN. TRPA1‐mediated responses in trigeminal sensory neurons: Interaction between TRPA1 and TRPV1. Eur J Neurosci 29: 1568‐1578, 2009.
 153. Schaefer M. Homo‐ and heteromeric assembly of TRP channel subunits. Pflugers Arch 451: 35‐42, 2005.
 154. Schoppa NE, McCormack K, Tanouye MA, Sigworth FJ. The size of gating charge in wild‐type and mutant Shaker potassium channels. Science 255: 1712‐1715, 1992.
 155. Schoppa NE, Sigworth FJ. Activation of Shaker potassium channels. III. An activation gating model for wild‐type and V2 mutant channels. J Gen Physiol 111: 313‐342, 1998.
 156. Sedgwick SG, Smerdon SJ. The ankyrin repeat: A diversity of interactions on a common structural framework. Trends Biochem Sci 24: 311‐316, 1999.
 157. Semtner M, Schaefer M, Pinkenburg O, Plant TD. Potentiation of TRPC5 by protons. J Biol Chem 282: 33868‐33878, 2007.
 158. Sharif Naeini R, Witty MF, Seguela P, Bourque CW. An N‐terminal variant of Trpv1 channel is required for osmosensory transduction. Nat Neurosci 9: 93‐98, 2006.
 159. Sherkheli MA, Benecke H, Doerner JF, Kletke O, Vogt‐Eisele AK, Gisselmann G, Hatt H. Monoterpenoids induce agonist‐specific desensitization of transient receptor potential vanilloid‐3 (TRPV3) ion channels. J Pharm Pharm Sci 12: 116‐128, 2009.
 160. Sherkheli MA, Vogt‐Eisele AK, Bura D, Beltran Marques LR, Gisselmann G, Hatt H. Characterization of selective TRPM8 ligands and their structure activity response (S.A.R) relationship. J Pharm Pharm Sci 13: 242‐253, 2010.
 161. Shigematsu H, Sokabe T, Danev R, Tominaga M, Nagayama K. A 3.5‐nm structure of rat TRPV4 cation channel revealed by Zernike phase‐contrast cryoelectron microscopy. J Biol Chem 285: 11210‐11218, 2010.
 162. Shimizu T, Janssens A, Voets T, Nilius B. Regulation of the murine TRPP3 channel by voltage, pH, and changes in cell volume. Pflugers Arch 457: 795‐807, 2009.
 163. Shuart NG, Haitin Y, Camp SS, Black KD, Zagotta WN. Molecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide‐gated ion channels. Nat Commun 2: 457, 2011.
 164. Sigworth FJ. Voltage gating of ion channels. Q Rev Biophys 27: 1‐40, 1994.
 165. Singh BB, Liu X, Tang J, Zhu MX, Ambudkar IS. Calmodulin regulates Ca(2+)‐dependent feedback inhibition of store‐operated Ca(2+) influx by interaction with a site in the C terminus of TrpC1. Mol Cell 9: 739‐750, 2002.
 166. Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, Wright JE, Jerman JC, Walhin JP, Ooi L, Egerton J, Charles KJ, Smart D, Randall AD, Anand P, Davis JB. TRPV3 is a temperature‐sensitive vanilloid receptor‐like protein. Nature 418: 186‐190, 2002.
 167. Sokolova O, Kolmakova‐Partensky L, Grigorieff N. Three‐dimensional structure of a voltage‐gated potassium channel at 2.5 nm resolution. Structure 9: 215‐220, 2001.
 168. Soyombo AA, Tjon‐Kon‐Sang S, Rbaibi Y, Bashllari E, Bisceglia J, Muallem S, Kiselyov K. TRP‐ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. J Biol Chem 281: 7294‐7301, 2006.
 169. 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 103: 16586‐16591, 2006.
 170. Spencer RH, Chang G, Rees DC. ‘Feeling the pressure’: Structural insights into a gated mechanosensitive channel. Curr Opin Struct Biol 9: 448‐454, 1999.
 171. Spyridaki A, Fritzsch G, Kouimtzoglou E, Baciou L, Ghanotakis D. The natural product capsaicin inhibits photosynthetic electron transport at the reducing side of photosystem II and purple bacterial reaction center: Structural details of capsaicin binding. Biochim Biophys Acta 1459: 69‐76, 2000.
 172. Stewart AP, Smith GD, Sandford RN, Edwardson JM. Atomic force microscopy reveals the alternating subunit arrangement of the TRPP2‐TRPV4 heterotetramer. Biophys J 99: 790‐797, 2010.
 173. Storch U, Forst AL, Philipp M, Gudermann T, Mederos YSM. TRPC1 reduces the calcium permeability in heteromeric channel complexes. J Biol Chem 287: 3530‐3540, 2011.
 174. 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 112: 819‐829, 2003.
 175. Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD. OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol 2: 695‐702, 2000.
 176. Strotmann R, Schultz G, Plant TD. Ca2+‐dependent potentiation of the nonselective cation channel TRPV4 is mediated by a C‐terminal calmodulin binding site. J Biol Chem 278: 26541‐26549, 2003.
 177. Strubing C, Krapivinsky G, Krapivinsky L, Clapham DE. TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 29: 645‐655, 2001.
 178. Strubing C, Krapivinsky G, Krapivinsky L, Clapham DE. Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem 278: 39014‐39019, 2003.
 179. Takahashi N, Mizuno Y, Kozai D, Yamamoto S, Kiyonaka S, Shibata T, Uchida K, Mori Y. Molecular characterization of TRPA1 channel activation by cysteine‐reactive inflammatory mediators. Channels (Austin) 2: 287‐298, 2008.
 180. 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 438: 1022‐1025, 2005.
 181. Tang J, Lin Y, Zhang Z, Tikunova S, Birnbaumer L, Zhu MX. Identification of common binding sites for calmodulin and inositol 1,4,5‐trisphosphate receptors on the carboxyl termini of trp channels. J Biol Chem 276: 21303‐21310, 2001.
 182. Tokumitsu H, Muramatsu M, Ikura M, Kobayashi R. Regulatory mechanism of Ca2+/calmodulin‐dependent protein kinase kinase. J Biol Chem 275: 20090‐20095, 2000.
 183. 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 21: 531‐543, 1998.
 184. Tribet C, Audebert R, Popot JL. Amphipols: Polymers that keep membrane proteins soluble in aqueous solutions. Proc Natl Acad Sci U S A 93: 15047‐15050, 1996.
 185. Trost C, Marquart A, Zimmer S, Philipp S, Cavalie A, Flockerzi V. Ca2+‐dependent interaction of the trpl cation channel and calmodulin. FEBS Lett 451: 257‐263, 1999.
 186. Trudeau MC, Zagotta WN. Calcium/calmodulin modulation of olfactory and rod cyclic nucleotide‐gated ion channels. J Biol Chem 278: 18705‐18708, 2003.
 187. Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, Sukhatme VP. Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci U S A 96: 3934‐3939, 1999.
 188. Tsuruda PR, Julius D, Minor DL, Jr. Coiled coils direct assembly of a cold‐activated TRP channel. Neuron 51: 201‐212, 2006.
 189. Ugawa S, Ueda T, Ishida Y, Nishigaki M, Shibata Y, Shimada S. Amiloride‐blockable acid‐sensing ion channels are leading acid sensors expressed in human nociceptors. J Clin Invest 110: 1185‐1190, 2002.
 190. Unwin N. Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol 346: 967‐989, 2005.
 191. Vaca L, Sampieri A. Calmodulin modulates the delay period between release of calcium from internal stores and activation of calcium influx via endogenous TRP1 channels. J Biol Chem 277: 42178‐42187, 2002.
 192. Varnum MD, Zagotta WN. Interdomain interactions underlying activation of cyclic nucleotide‐gated channels. Science 278: 110‐113, 1997.
 193. Venkatachalam K, Hofmann T, Montell C. Lysosomal localization of TRPML3 depends on TRPML2 and the mucolipidosis‐associated protein TRPML1. J Biol Chem 281: 17517‐17527, 2006.
 194. Vennekens R, Voets T, Bindels RJ, Droogmans G, Nilius B. Current understanding of mammalian TRP homologues. Cell Calcium 31: 253‐264, 2002.
 195. Vlachova V, Teisinger J, Susankova K, Lyfenko A, Ettrich R, Vyklicky L. Functional role of C‐terminal cytoplasmic tail of rat vanilloid receptor 1. J Neurosci 23: 1340‐1350, 2003.
 196. Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B. The principle of temperature‐dependent gating in cold‐ and heat‐sensitive TRP channels. Nature 430: 748‐754, 2004.
 197. Voets T, Owsianik G, Janssens A, Talavera K, Nilius B. TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli. Nat Chem Biol 3: 174‐182, 2007.
 198. Vogt‐Eisele AK, Weber K, Sherkheli MA, Vielhaber G, Panten J, Gisselmann G, Hatt H. Monoterpenoid agonists of TRPV3. Br J Pharmacol 151: 530‐540, 2007.
 199. Vriens J, Watanabe H, Janssens A, Droogmans G, Voets T, Nilius B. Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4. Proc Natl Acad Sci U S A 101: 396‐401, 2004.
 200. Wang L, Wang DH. TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation 112: 3617‐3623, 2005.
 201. Warr CG, Kelly LE. Identification and characterization of two distinct calmodulin‐binding sites in the Trpl ion‐channel protein of Drosophila melanogaster. Biochem J 314(Pt 2): 497‐503, 1996.
 202. Wedel BJ, Vazquez G, McKay RR, St JBG, Putney JW, Jr. A calmodulin/inositol 1,4,5‐trisphosphate (IP3) receptor‐binding region targets TRPC3 to the plasma membrane in a calmodulin/IP3 receptor‐independent process. J Biol Chem 278: 25758‐25765, 2003.
 203. Wegierski T, Lewandrowski U, Muller B, Sickmann A, Walz G. Tyrosine phosphorylation modulates the activity of TRPV4 in response to defined stimuli. J Biol Chem 284: 2923‐2933, 2009.
 204. Wei C, Wang X, Chen M, Ouyang K, Song LS, Cheng H. Calcium flickers steer cell migration. Nature 457: 901‐905, 2009.
 205. Wei ET, Seid DA. AG‐3‐5: A chemical producing sensations of cold. J Pharm Pharmacol 35: 110‐112, 1983.
 206. Weitz D, Ficek N, Kremmer E, Bauer PJ, Kaupp UB. Subunit stoichiometry of the CNG channel of rod photoreceptors. Neuron 36: 881‐889, 2002.
 207. Welch JM, Simon SA, Reinhart PH. The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat. Proc Natl Acad Sci U S A 97: 13889‐13894, 2000.
 208. Wharton J, Gulbenkian S, Mulderry PK, Ghatei MA, McGregor GP, Bloom SR, Polak JM. Capsaicin induces a depletion of calcitonin gene‐related peptide (CGRP)‐immunoreactive nerves in the cardiovascular system of the guinea pig and rat. J Auton Nerv Syst 16: 289‐309, 1986.
 209. Wissenbach U, Bodding M, Freichel M, Flockerzi V. Trp12, a novel Trp related protein from kidney. FEBS Lett 485: 127‐134, 2000.
 210. Wu L, Gao X, Brown RC, Heller S, O'Neil RG. Dual role of the TRPV4 channel as a sensor of flow and osmolality in renal epithelial cells. Am J Physiol Renal Physiol 293: F1699‐F1713, 2007.
 211. Wu LJ, Sweet TB, Clapham DE. International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol Rev 62: 381‐404, 2010.
 212. Xia XM, Fakler B, Rivard A, Wayman G, Johnson‐Pais T, Keen JE, Ishii T, Hirschberg B, Bond CT, Lutsenko S, Maylie J, Adelman JP. Mechanism of calcium gating in small‐conductance calcium‐activated potassium channels. Nature 395: 503‐507, 1998.
 213. Xiao B, Coste B, Mathur J, Patapoutian A. Temperature‐dependent STIM1 activation induces Ca(2)+ influx and modulates gene expression. Nat Chem Biol 7: 351‐358, 2011.
 214. Xiao R, Tang J, Wang C, Colton CK, Tian J, Zhu MX. Calcium plays a central role in the sensitization of TRPV3 channel to repetitive stimulations. J Biol Chem 283: 6162‐6174, 2008.
 215. Xu H, Delling M, Jun JC, Clapham DE. Oregano, thyme and clove‐derived flavors and skin sensitizers activate specific TRP channels. Nat Neurosci 9: 628‐635, 2006.
 216. Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, Ge P, Lilly J, Silos‐Santiago I, Xie Y, DiStefano PS, Curtis R, Clapham DE. TRPV3 is a calcium‐permeable temperature‐sensitive cation channel. Nature 418: 181‐186, 2002.
 217. Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM. Regulation of a transient receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinase‐dependent tyrosine phosphorylation of TRPV4 on TYR‐253 mediates its response to hypotonic stress. J Biol Chem 278: 11520‐11527, 2003.
 218. Yamaguchi H, Matsushita M, Nairn AC, Kuriyan J. Crystal structure of the atypical protein kinase domain of a TRP channel with phosphotransferase activity. Mol Cell 7: 1047‐1057, 2001.
 219. Yang F, Cui Y, Wang K, Zheng J. Thermosensitive TRP channel pore turret is part of the temperature activation pathway. Proc Natl Acad Sci U S A 107: 7083‐7088, 2010.
 220. Yao J, Liu B, Qin F. Kinetic and energetic analysis of thermally activated TRPV1 channels. Biophys J 99: 1743‐1753.
 221. Yao J, Liu B, Qin F. Rapid temperature jump by infrared diode laser irradiation for patch‐clamp studies. Biophys J 96: 3611‐3619, 2009.
 222. Yao J, Liu B, Qin F. Modular thermal sensors in temperature‐gated transient receptor potential (TRP) channels. Proc Natl Acad Sci U S A 108: 11109‐11114, 2011.
 223. Yeh BI, Kim YK, Jabbar W, Huang CL. Conformational changes of pore helix coupled to gating of TRPV5 by protons. EMBO J 24: 3224‐3234, 2005.
 224. Yeh BI, Sun TJ, Lee JZ, Chen HH, Huang CL. Mechanism and molecular determinant for regulation of rabbit transient receptor potential type 5 (TRPV5) channel by extracellular pH. J Biol Chem 278: 51044‐51052, 2003.
 225. Yellen G. The moving parts of voltage‐gated ion channels. Q Rev Biophys 31: 239‐295, 1998.
 226. Yildirim E, Dietrich A, Birnbaumer L. The mouse C‐type transient receptor potential 2 (TRPC2) channel: Alternative splicing and calmodulin binding to its N terminus. Proc Natl Acad Sci U S A 100: 2220‐2225, 2003.
 227. Yu Y, Ulbrich MH, Li MH, Buraei Z, Chen XZ, Ong AC, Tong L, Isacoff EY, Yang J. Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proc Natl Acad Sci U S A 106: 11558‐11563, 2009.
 228. Zagotta WN, Hoshi T, Dittman J, Aldrich RW. Shaker potassium channel gating. II: Transitions in the activation pathway. J Gen Physiol 103: 279‐319, 1994.
 229. Zagotta WN, Olivier NB, Black KD, Young EC, Olson R, Gouaux E. Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature 425: 200‐205, 2003.
 230. Zagranichnaya TK, Wu X, Villereal ML. Endogenous TRPC1, TRPC3, and TRPC7 proteins combine to form native store‐operated channels in HEK‐293 cells. J Biol Chem 280: 29559‐29569, 2005.
 231. Zakharian E, Cao C, Rohacs T. Gating of transient receptor potential melastatin 8 (TRPM8) channels activated by cold and chemical agonists in planar lipid bilayers. J Neurosci 30: 12526‐12534, 2010.
 232. Zakharian E, Thyagarajan B, French RJ, Pavlov E, Rohacs T. Inorganic polyphosphate modulates TRPM8 channels. PLoS One 4: e5404, 2009.
 233. Zhang F, Liu S, Yang F, Zheng J, Wang K. Identification of a tetrameric assembly domain in the C terminus of heat‐activated TRPV1 channels. J Biol Chem 286: 15308‐15316, 2011.
 234. Zhang P, Luo Y, Chasan B, Gonzalez‐Perrett S, Montalbetti N, Timpanaro GA, Cantero Mdel R, Ramos AJ, Goldmann WH, Zhou J, Cantiello HF. The multimeric structure of polycystin‐2 (TRPP2): Structural‐functional correlates of homo‐ and hetero‐multimers with TRPC1. Hum Mol Genet 18: 1238‐1251, 2009.
 235. Zhang Z, Tang J, Tikunova S, Johnson JD, Chen Z, Qin N, Dietrich A, Stefani E, Birnbaumer L, Zhu MX. Activation of Trp3 by inositol 1,4,5‐trisphosphate receptors through displacement of inhibitory calmodulin from a common binding domain. Proc Natl Acad Sci U S A 98: 3168‐3173, 2001.
 236. Zheng J, Trudeau MC, Zagotta WN. Rod cyclic nucleotide‐gated channels have a stoichiometry of three CNGA1 subunits and one CNGB1 subunit. Neuron 36: 891‐896, 2002.
 237. Zhong H, Molday LL, Molday RS, Yau KW. The heteromeric cyclic nucleotide‐gated channel adopts a 3A:1B stoichiometry. Nature 420: 193‐198, 2002.
 238. Zhong L, Bellemer A. Thermosensory and nonthermosensory isoforms of Drosophila melanogaster TRPA1 reveal heat‐sensor domains of a thermoTRP channel. Cell Reports 1: 43‐55, 2012.
 239. Zhu MX. Multiple roles of calmodulin and other Ca(2+)‐binding proteins in the functional regulation of TRP channels. Pflugers Arch 451: 105‐115, 2005.
 240. Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birnbaumer L. trp, a novel mammalian gene family essential for agonist‐activated capacitative Ca2+ entry. Cell 85: 661‐671, 1996.
 241. Zimmermann K, Lennerz JK, Hein A, Link AS, Kaczmarek JS, Delling M, Uysal S, Pfeifer JD, Riccio A, Clapham DE. Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold‐transducer in the peripheral nervous system. Proc Natl Acad Sci U S A 108: 18114‐18119, 2011.
 242. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400: 452‐457, 1999.
Further Reading
 1. Bertil Hille, Ion Channels of Excitable Membranes (3rd ed). Sunderland: Sinauer Associates, Inc., 2001.

Further Reading

Bertil Hille, Ion Channels of Excitable Membranes, 3rd edition, 2001, Sinauer Associates, Inc., Sunderland


Related Articles:

Membrane Transport in Single Cells
Pain and Nociception
Mechanisms of Transmembrane Signaling
Integrated Physiological Mechanisms of Exercise Performance, Adaptation, and Maladaptation to Heat Stress
TRP Channels

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Jie Zheng. Molecular Mechanism of TRP Channels. Compr Physiol 2013, 3: 221-242. doi: 10.1002/cphy.c120001