Figure 1. Mammalian TRP ion channel family tree. The branch lengths in point accepted mutations (PAM, the mean number of substitutions per 100 residues) shows the evolutionary distance. DAG, diacylglycerol. Modified from Clapham DE (2003) TRP channels as cellular sensors. Nature 426: 517-524.
Figure 2. TRP channel domains. TRP channels have a predicted 6 transmembrane topology (S1-S6) with a pore loop between S5 and S6. The cytoplasmic N- and C-termini contain different structural and functional elements as indicated for each subfamily. TRP Box, EWKFAR in TRPCs; AnkR, ankyrin repeats (number differs by subfamily members); CC, coiled-coil domain (position in the cytoplasmic termini varies); S/T Kinase, serine/threonine kinase intrinsic to TRPM6 and TRPM7; CIRB, calmodulin- and inositol triphosphate receptor (InsP3R)-binding site; PDZ, amino acid motif binding PDZ domains (TRPV3 contains a consensus PDZ binding motif); NUDIX, NUDT9 homology domain binding ADP ribose (ADPR) or ADPR-2'-phosphate (ADPRP); EF Hand, canonical Ca2+-binding domain in TRPP1/PKD2 (EF Hand sequence motif in TRPA1 not shown); ER retention, endoplasmic reticulum retention signal. The TRPM Homology Region is of unknown function. Modified from Clapham DE (2003) TRP channels as cellular sensors. Nature 426: 517-524.
Figure 3. TRPV1 structure. A, B) Ribbon diagrams showing the TRPV1 structure in the apo (closed) state in side view (A) or bottom view (B). Subunits in A and B are color-coded. C) TRPV1 pore with marked ion permeation pathway. The two sites of constriction highlighting the upper and lower gate are indicated. From Liao et al. (2013) Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504:107-112, with permission.
TRP channel | Channelopathy | OMIM |
TRPC6 | Glomerulosclerosis, focal segmental, 2 | 603965 |
TRPV3 | Olmsted Syndrome | 614594 |
TRPV4 | Brachyolmia type 3 | 113500 |
Digital arthropathy-brachydactyly, familial | 606835 | |
Hereditary motor and sensory neuropathy, type IIc | 606071 | |
Metatropic dysplasia | 156530 | |
Parastremmatic dwarfism | 168400 | |
Scapuloperoneal spinal muscular atrophy | 181405 | |
SED, Maroteaux type | 184095 | |
Spinal muscular atrophy, distal, congenital nonprogressive | 600175 | |
Spondylometaphyseal dysplasia, Kozlowski type | 184252 | |
TRPM1 | Night blindness, congenital stationary (complete), 1C, autosomal recessive | 613216 |
TRPM4 | Progressive familial heart block, type IB | 604559 |
TRPM6 | Hypomagnesemia 1, intestinal | 602014 |
TRPA1 | Episodic pain syndrome, familial | 615040 |
TRPML1 | Mucolipidosis IV | 252650 |
PKD2 (TRPP1) | Autosomal dominant polycystic kidney disease | 613095 |
1. Ambudkar IS, Ong HL. (2007) Organization and function of TRPC channelosomes. Pflugers Arch, 455 (2): 187-200. [PMID:17486362]
2. Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A. (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron, 41 (6): 849-57. [PMID:15046718]
3. Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D. (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell, 124 (6): 1269-82. [PMID:16564016]
4. Bautista DM, Movahed P, Hinman A, Axelsson HE, Sterner O, Högestätt ED, Julius D, Jordt SE, Zygmunt PM. (2005) Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci USA, 102 (34): 12248-52. [PMID:16103371]
5. Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D. (2007) The menthol receptor TRPM8 is the principal detector of environmental cold. Nature, 448 (7150): 204-8. [PMID:17538622]
6. Bork P. (1993) Hundreds of ankyrin-like repeats in functionally diverse proteins: mobile modules that cross phyla horizontally?. Proteins, 17 (4): 363-74. [PMID:8108379]
7. Cao E, Liao M, Cheng Y, Julius D. (2013) TRPV1 structures in distinct conformations reveal activation mechanisms. Nature, 504 (7478): 113-8. [PMID:24305161]
8. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 288 (5464): 306-13. [PMID:10764638]
9. Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D. (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature, 398 (6726): 436-41. [PMID:10201375]
10. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature, 389 (6653): 816-24. [PMID:9349813]
11. Catterall WA. (2010) Ion channel voltage sensors: structure, function, and pathophysiology. Neuron, 67 (6): 915-28. [PMID:20869590]
12. Cheng KT, Ong HL, Liu X, Ambudkar IS. (2011) Contribution of TRPC1 and Orai1 to Ca(2+) entry activated by store depletion. Adv Exp Med Biol, 704: 435-49. [PMID:21290310]
13. Chuang HH, Neuhausser WM, Julius D. (2004) The super-cooling agent icilin reveals a mechanism of coincidence detection by a temperature-sensitive TRP channel. Neuron, 43 (6): 859-69. [PMID:15363396]
14. Chubanov V, Waldegger S, Mederos y Schnitzler M, Vitzthum H, Sassen MC, Seyberth HW, Konrad M, Gudermann T. (2004) Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proc Natl Acad Sci USA, 101 (9): 2894-9. [PMID:14976260]
15. Clapham DE. (2003) TRP channels as cellular sensors. Nature, 426 (6966): 517-24. [PMID:14654832]
16. Clapham DE. (2015) Structural biology: Pain-sensing TRPA1 channel resolved. Nature, 520 (7548): 439-41. [PMID:25855290]
17. Clapham DE, Garbers DL. (2005) International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels. Pharmacol Rev, 57 (4): 451-4. [PMID:16382101]
18. Clapham DE, Miller C. (2011) A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc Natl Acad Sci U S A, 108 (49): 19492-7. [PMID:22109551]
19. Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A. (2010) Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science, 330 (6000): 55-60. [PMID:20813920]
20. Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS, Kim SE, Schmidt M, Mathur J, Dubin AE et al.. (2012) Piezo proteins are pore-forming subunits of mechanically activated channels. Nature, 483 (7388): 176-81. [PMID:22343900]
21. Erler I, Hirnet D, Wissenbach U, Flockerzi V, Niemeyer BA. (2004) Ca2+-selective transient receptor potential V channel architecture and function require a specific ankyrin repeat. J Biol Chem, 279 (33): 34456-63. [PMID:15192090]
22. Everaerts W, Zhen X, Ghosh D, Vriens J, Gevaert T, Gilbert JP, Hayward NJ, McNamara CR, Xue F, Moran MM et al.. (2010) Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci USA, 107 (44): 19084-9. [PMID:20956320]
23. Feng Q. (2014) Temperature sensing by thermal TRP channels: thermodynamic basis and molecular insights. Curr Top Membr, 74: 19-50. [PMID:25366232]
24. Gees M, Owsianik G, Nilius B, Voets T. (2012) TRP channels. Compr Physiol, 2 (1): 563-608. [PMID:23728980]
25. Guler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M. (2002) Heat-evoked activation of the ion channel, TRPV4. J Neurosci, 22 (15): 6408-14. [PMID:12151520]
26. Huynh KW, Cohen MR, Jiang J, Samanta A, Lodowski DT, Zhou ZH, Moiseenkova-Bell VY. (2016) Structure of the full-length TRPV2 channel by cryo-EM. Nat Commun, 7: 11130. [PMID:27021073]
27. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Högestätt ED, Meng ID, Julius D. (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature, 427 (6971): 260-5. [PMID:14712238]
28. Karashima Y, Talavera K, Everaerts W, Janssens A, Kwan KY, Vennekens R, Nilius B, Voets T. (2009) TRPA1 acts as a cold sensor in vitro and in vivo. Proc Natl Acad Sci USA, 106 (4): 1273-8. [PMID:19144922]
29. Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR et al.. (2011) Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clin Invest, 121 (12): 4796-809. [PMID:22105175]
30. Lainez S, Schlingmann KP, van der Wijst J, Dworniczak B, van Zeeland F, Konrad M, Bindels RJ, Hoenderop JG. (2014) New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. Eur J Hum Genet, 22 (4): 497-504. [PMID:23942199]
31. Levina N, Tötemeyer S, Stokes NR, Louis P, Jones MA, Booth IR. (1999) Protection of Escherichia coli cells against extreme turgor by activation of MscS and MscL mechanosensitive channels: identification of genes required for MscS activity. EMBO J, 18 (7): 1730-7. [PMID:10202137]
32. Leypold BG, Yu CR, Leinders-Zufall T, Kim MM, Zufall F, Axel R. (2002) Altered sexual and social behaviors in trp2 mutant mice. Proc Natl Acad Sci U S A, 99 (9): 6376-81. [PMID:11972034]
33. Liao M, Cao E, Julius D, Cheng Y. (2013) Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature, 504 (7478): 107-12. [PMID:24305160]
34. Liman ER, Corey DP, Dulac C. (1999) TRP2: a candidate transduction channel for mammalian pheromone sensory signaling. Proc Natl Acad Sci USA, 96 (10): 5791-6. [PMID:10318963]
35. Long SB, Campbell EB, Mackinnon R. (2005) Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science, 309 (5736): 897-903. [PMID:16002581]
36. Long SB, Tao X, Campbell EB, MacKinnon R. (2007) Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature, 450 (7168): 376-82. [PMID:18004376]
37. Loukin S, Su Z, Kung C. (2011) Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations. PLoS One, 6 (5): e19533. [PMID:21573172]
38. McKemy DD, Neuhausser WM, Julius D. (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature, 416 (6876): 52-8. [PMID:11882888]
39. McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM et al.. (2007) TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci USA, 104 (33): 13525-30. [PMID:17686976]
40. Montell C, Rubin GM. (1989) Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron, 2 (4): 1313-23. [PMID:2516726]
41. Nadler MJ, Hermosura MC, Inabe K, Perraud AL, Zhu Q, Stokes AJ, Kurosaki T, Kinet JP, Penner R, Scharenberg AM et al.. (2001) LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability. Nature, 411 (6837): 590-5. [PMID:11385574]
42. Nilius B, Owsianik G. (2010) Transient receptor potential channelopathies. Pflugers Arch, 460 (2): 437-50. [PMID:20127491]
43. Nilius B, Owsianik G, Voets T. (2008) Transient receptor potential channels meet phosphoinositides. EMBO J, 27 (21): 2809-16. [PMID:18923420]
44. Nilius B, Talavera K, Owsianik G, Prenen J, Droogmans G, Voets T. (2005) Gating of TRP channels: a voltage connection?. J Physiol (Lond.), 567 (Pt 1): 35-44. [PMID:15878939]
45. Nilius B, Voets T. (2013) The puzzle of TRPV4 channelopathies. EMBO Rep, 14 (2): 152-63. [PMID:23306656]
46. Nishimura G, Lausch E, Savarirayan R, Shiba M, Spranger J, Zabel B, Ikegawa S, Superti-Furga A, Unger S. (2012) TRPV4-associated skeletal dysplasias. Am J Med Genet C Semin Med Genet, 160C (3): 190-204. [PMID:22791502]
47. Oancea E, Vriens J, Brauchi S, Jun J, Splawski I, Clapham DE. (2009) TRPM1 forms ion channels associated with melanin content in melanocytes. Sci Signal, 2 (70): ra21. [PMID:19436059]
48. Ong AC, Harris PC. (2015) A polycystin-centric view of cyst formation and disease: the polycystins revisited. Kidney Int, 88 (4): 699-710. [PMID:26200945]
49. Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D. (2015) Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature, 520 (7548): 511-7. [PMID:25855297]
50. Pedersen SF, Owsianik G, Nilius B. (2005) TRP channels: an overview. Cell Calcium, 38 (3-4): 233-52. [PMID:16098585]
51. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S et al.. (2002) A TRP channel that senses cold stimuli and menthol. Cell, 108 (5): 705-15. [PMID:11893340]
52. Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P et al.. (2002) A heat-sensitive TRP channel expressed in keratinocytes. Science, 296 (5575): 2046-9. [PMID:12016205]
53. PKD Foundation. Autosomal Dominant Polycystic Kidney Disease Mutation Database: PKDB. Accessed on 24/08/2021. Modified on 24/08/2021. pkdb.mayo.edu, http://pkdb.mayo.edu
54. Plant TD. (2014) TRPs in mechanosensing and volume regulation. Handb Exp Pharmacol, 223: 743-66. [PMID:24961968]
55. Potier M, Trebak M. (2008) New developments in the signaling mechanisms of the store-operated calcium entry pathway. Pflugers Arch, 457 (2): 405-15. [PMID:18536932]
56. Ramsey IS, Delling M, Clapham DE. (2006) An introduction to TRP channels. Annu Rev Physiol, 68: 619-47. [PMID:16460286]
57. Rohacs T, Nilius B. (2007) Regulation of transient receptor potential (TRP) channels by phosphoinositides. Pflugers Arch, 455 (1): 157-68. [PMID:17479281]
58. Runnels LW, Yue L, Clapham DE. (2001) TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science, 291 (5506): 1043-7. [PMID:11161216]
59. Salido GM, Sage SO, Rosado JA. (2009) TRPC channels and store-operated Ca(2+) entry. Biochim Biophys Acta, 1793 (2): 223-30. [PMID:19061922]
60. Schaefer M, Plant TD, Obukhov AG, Hofmann T, Gudermann T, Schultz G. (2000) Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. J Biol Chem, 275 (23): 17517-26. [PMID:10837492]
61. Schlingmann KP, Sassen MC, Weber S, Pechmann U, Kusch K, Pelken L, Lotan D, Syrrou M, Prebble JJ, Cole DE et al.. (2005) Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia. J Am Soc Nephrol, 16 (10): 3061-9. [PMID:16107578]
62. Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D et al.. (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet, 31 (2): 166-70. [PMID:12032568]
63. Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, Wright JE, Jerman JC, Walhin JP, Ooi L et al.. (2002) TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature, 418 (6894): 186-90. [PMID:12077606]
64. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW et al.. (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell, 112 (6): 819-29. [PMID:12654248]
65. Stowers L, Holy TE, Meister M, Dulac C, Koentges G. (2002) Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science, 295 (5559): 1493-500. [PMID:11823606]
66. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE. (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron, 29 (3): 645-55. [PMID:11301024]
67. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE. (2003) Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem, 278 (40): 39014-9. [PMID:12857742]
68. Sukharev S. (2002) Purification of the small mechanosensitive channel of Escherichia coli (MscS): the subunit structure, conduction, and gating characteristics in liposomes. Biophys J, 83 (1): 290-8. [PMID:12080120]
69. Sukharev SI, Blount P, Martinac B, Blattner FR, Kung C. (1994) A large-conductance mechanosensitive channel in E. coli encoded by mscL alone. Nature, 368 (6468): 265-8. [PMID:7511799]
70. Talavera K, Yasumatsu K, Voets T, Droogmans G, Shigemura N, Ninomiya Y, Margolskee RF, Nilius B. (2005) Heat activation of TRPM5 underlies thermal sensitivity of sweet taste. Nature, 438 (7070): 1022-5. [PMID:16355226]
71. Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian MY, Costell M, Maniscalco-Hauk K, Krawiec JA, Olzinski A et al.. (2012) An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med, 4 (159): 159ra148. [PMID:23136043]
72. Thorneloe KS, Sulpizio AC, Lin Z, Figueroa DJ, Clouse AK, McCafferty GP, Chendrimada TP, Lashinger ES, Gordon E, Evans L et al.. (2008) N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I. J Pharmacol Exp Ther, 326 (2): 432-42. [PMID:18499743]
73. Tóth B, Iordanov I, Csanády L. (2015) Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2'-phosphate. J Gen Physiol, 145 (5): 419-30. [PMID:25918360]
74. Tóth BI, Nilius B. (2015) Transient Receptor Potential Dysfunctions in Hereditary Diseases: TRP Channelopathies and Beyond. In TRP Channels as Therapeutic Target Edited by Szallasi A (Elsevier Inc) 13-33. DOI: 10.1016/C2013-0-09923-9 [ISBN:9780124200241]
75. Venkatachalam K, Montell C. (2007) TRP channels. Annu Rev Biochem, 76: 387-417. [PMID:17579562]
76. Vriens J, Owsianik G, Hofmann T, Philipp SE, Stab J, Chen X, Benoit M, Xue F, Janssens A, Kerselaers S et al.. (2011) TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron, 70 (3): 482-94. [PMID:21555074]
77. Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger MB, Beck GE, Englehardt RK, Carmi R et al.. (2002) Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet, 31 (2): 171-4. [PMID:12032570]
78. Watanabe H, Vriens J, Suh SH, Benham CD, Droogmans G, Nilius B. (2002) Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. J Biol Chem, 277 (49): 47044-51. [PMID:12354759]
79. Wu G, Markowitz GS, Li L, D'Agati VD, Factor SM, Geng L, Tibara S, Tuchman J, Cai Y, Park JH et al.. (2000) Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat Genet, 24 (1): 75-8. [PMID:10615132]
80. Wu LJ, Sweet TB, Clapham DE. (2010) International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol Rev, 62 (3): 381-404. [PMID:20716668]
81. Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, Ge P, Lilly J, Silos-Santiago I, Xie Y et al.. (2002) TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature, 418 (6894): 181-6. [PMID:12077604]
82. Xu H, Ren D. (2015) Lysosomal physiology. Annu Rev Physiol, 77: 57-80. [PMID:25668017]
83. Yuan JP, Kim MS, Zeng W, Shin DM, Huang G, Worley PF, Muallem S. (2009) TRPC channels as STIM1-regulated SOCs. Channels (Austin), 3 (4): 221-5. [PMID:19574740]
84. Zimmermann K, Lennerz JK, Hein A, Link AS, Kaczmarek JS, Delling M, Uysal S, Pfeifer JD, Riccio A, Clapham DE. (2011) Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system. Proc Natl Acad Sci USA, 108 (44): 18114-9. [PMID:22025699]
85. Zubcevic L, Herzik Jr MA, Chung BC, Liu Z, Lander GC, Lee SY. (2016) Cryo-electron microscopy structure of the TRPV2 ion channel. Nat Struct Mol Biol, 23 (2): 180-186. [PMID:26779611]