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OtherIUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. XLIX. Nomenclature and Structure-Function Relationships of Transient Receptor Potential Channels

David E. Clapham, David Julius, Craig Montell and Günter Schultz
Pharmacological Reviews December 2005, 57 (4) 427-450; DOI: https://doi.org/10.1124/pr.57.4.6

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Alignment of human TRP family proteins using maximum parsimony analysis of the minimal pore regions. The tree was rooted to the bacterial NaChBac (not shown). The CatSper and TPC channels are discussed in “International Union of Pharmacology. L. Nomenclature and Structure-Function Relationships of CatSper and Two-Pore Channels.” Figure modified slightly from Yu and Catterall (2004).

Tables

  • TABLE 1

    TRPC1 channel

    Channel name TRPC11,2,3,4,5,6,7,8
    Description Nonselective cation channel subunit
    Other names TRP1
    Molecular information Human unigene: Hs0.250687, chr. 3q22–3q24
    Mouse unigene: Mm0.149633
    Associated subunits TRPC4, TRPC5 (TRPC3–embryo), calmodulin, IP3Rs, caveolin-1, Gq/11, PMCA, mGluR1
    Functional assays Patch-clamp, calcium imaging
    Current Outwardly rectifying when coexpressed with TRPC4 and TRPC5
    Conductance Not established
    Ion selectivity PNa/PCa ∼1:1 (when coexpressed with TRPC4 and TRPC5)5
    Activation Stretch?
    Inactivation Not established
    Activators Recording of Gq-coupled receptor (heteromer TRPC1/TRPC5), whole cell current, augmented store-operated influx as presumed homomer; no direct agonists identified, gated in response to stimulation of the Gq-coupled receptors, augmented by La3+ (heteromer of TRPC1 with TRPC4 or TRPC5)5; it has been proposed that the mGluR1-evoked slow EPSC is mediated by the TRPC1 cation channel; TRPC1 is expressed in perisynaptic regions of the cerebellar parallel fiber-Purkinje cell synapse and may be physically associated with mGluR16
    Gating inhibitors None
    Blockers Inhibited by 80 μM 2-APB (heteromer) and Gd3+
    Radioligands None
    Channel distribution Widely expressed; highest levels in brain, heart, kidney, lung, skeletal muscle, prostate, skin testis, ovaries
    Physiological functions Putative role in receptor-mediated, Ca2+-dependent secretion and contraction
    Mutations and pathophysiology Not established
    Pharmacological significance Involved in Ca2+ entry induced by phospholipid hydrolysis (PI response) and Ca2+ store depletion
    Comments Splice variants in human and mouse

    • chr., chromosome; PMCA, plasma membrane calcium pump; EPSC, excitatory postsynaptic current; PI, phosphatidylinositol.

    • ↵1. Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stettten G, and Montell C (1995) TRPC1, a human homolog of a Drosophila store-operated channel. Proc Natl Acad Sci USA 92:9652-9656

    • ↵2. Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, and Birnbaumer L (1996) trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell 85:661-671

    • ↵3. Zitt C, Zobel A, Obukhov AG, Harteneck C, Kalkbrenner F, Luckhoff A, and Schultz G (1996) Cloning and functional expression of a human Ca2+-permeable cation channel activated by calcium store depletion. Neuron 16:1189-1196

    • ↵4. Lintschinger B, Balzer-Geldsetzer M, Baskaran T, Graier WF, Romanin C, Zhu MX, and Groschner K (2000) Coassembly of Trp1 and Trp3 proteins generates diacylglycerol- and Ca2+-sensitive cation channels. J Biol Chem 275:27799-27805

    • ↵5. Strübing C, Krapivinsky G, Krapivinsky L, and Clapham DE (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 29:645-655

    • ↵6. Xu XZ, Li HS, Guggino WB, and Montell C (1997) Coassembly of TRP and TRPL produces a distinct store-operated conductance. Cell 89:1155-1164

    • ↵7. Brazer SC, Singh BB, Liu X, Swaim W, and Ambudkar IS (2003) Caveolin-1 contributes to assembly of store-operated Ca2+ influx channels by regulating plasma membrane localization of TRPC1. J Biol Chem 278:27208-27215

    • ↵8. Kim SJ, Kim YS, Yuan JP, Petralia RS, Worley PF, and Linden DJ (2003) Activation of the TRPC1 cation channel by metabotropic glutamate receptor mGluR1. Nature (Lond) 426:285–291</.>

  • TABLE 2

    TRPC2 channel

    Channel name TRPC21,2,3,4,5,6,7
    Description Mouse pheromone channel
    Other names mTrp2 (in mouse)
    Molecular information Human unigene: Hs0.131910 probable pseudogene, chr. 0.7
    Mouse unigene: Mm0.292904, chr. 11p15.4-p15.3
    Associated subunits Not established
    Functional assays Patch-clamp
    Current Near linear, nonselective cation conductance
    Conductance 42pS (symmetrical 140 Na+)7
    Ion selectivity Cation nonselective
    Activation Indirect via pheromone receptors
    Inactivation Not established
    Activators DAGs (10–100 μM)
    Gating inhibitors None
    Blockers None
    Radioligands None
    Channel distribution Vomeronasal organ, testis, heart, kidney, brain, sperm
    Physiological functions Sensory transduction in vomeronasal organ, possible role in acrosome reaction in sperm
    Mutations and pathophysiology TRPC2-deficient mice display abnormal mating behavior
    Pharmacological significance Candidate for mammalian pheromone sensory signaling
    Comments Human and bovine versions are likely to be pseudogenes2; the murine channel is expressed as multiple splice variants

    • chr., chromosome.

    • ↵1. Liman E, Corey DP, and Dulac C (1999) TRP2: a candidate transduction channel for mammalian pheromone sensory signaling. Proc Natl Acad Sci USA 96:5791-5796

    • ↵2. Vannier B, Peyton M, Boulay G, Brown D, Qin N, Jiang M, Zhu X, and Birnbaumer L (1999) Mouse trp2, the homologue of the human trpc2 pseudogene, encodes mTrp2, a store depletion-activated capacitative Ca2+ entry channel. Proc Natl Acad Sci USA 96:2060-2064

    • ↵3. Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stetten G, and Montell C (1995) TRPC1, a human homolog of a Drosophila store-operated channel. Proc Natl Acad Sci USA 92:9652-9656

    • ↵4. Hofmann T, Schaefer M, Schultz G, and Gudermann T (2000) Cloning, expression and subcellular localization of two novel splice variants of mouse transient receptor potential channel 2. Biochem J 351:115-122

    • ↵5. Jungnickel MK, Marrero H, Birnbaumer L, Lemos JR, and Florman HM (2001) Trp2 regulates entry of Ca2+ into mouse sperm triggered by egg ZP3. Nat Cell Biol 3:499-502

    • ↵6. Stowers L, Holy TE, Meister M, Dulac C, and Koentges G (2002) Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science (Wash DC) 295:1493-1500

    • ↵7. Lucas P, Ukhanov K, Leinders-Zufall T, and Zufall F (2003) A diacylglycerol-gated cation channel in vomeronasal neuron dendrites is impaired in TRPC2 mutant mice: mechanism of pheromone transduction. Neuron 40:551-561

  • TABLE 3

    TRPC3 channel

    Channel name TRPC31,2,3,4,5,6
    Description Diacylglycerol-Ca2+-activated TRP channel
    Other names mTRPC3
    Molecular information Human unigene: Hs0.150981, chr. 4q27
    Mouse unigene: Mm0.74363, chr. 3
    Associated subunits TRPC6, TRPC7, FKBP12, VAMP2, syntaxin, SNAP, NCX1, TrkB
    Functional assays Patch-clamp, calcium imaging
    Current Inwardly and outwardly rectifying, nonselective cation current
    Conductance 66pS2
    Ion selectivity PNa/PCa = 1:1.5
    Activation Intracellular Ca2+
    Inactivation Not established
    Activators Activated either by DAG or direct interaction with the IP3 receptor in vitro; activated through a BDNF, TrkB-mediated pathway in neurons
    Gating inhibitors None
    Blockers 2-APB, 1–25 μM Gd3+, La3+, RuR
    Radioligands None
    Channel distribution Brain, placenta, heart, muscle, smooth muscle
    Physiological functions Resistance artery myogenic tone, airway regulation
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments DAG response is PKC-independent

    • chr., chromosome; TrkB, tyrosine kinase B; BDNF, brain-derived neurotrophic factor; RuR, ruthenium red.

    • ↵1. Hofmann T, Schaefer M, Schultz G, and Gudermann T (2002) Subunit composition of mammalian transient receptor potential channels in living cells. Proc Natl Acad Sci USA 99:7461-7466

    • ↵2. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, and Schultz G (1999) Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature (Lond) 397:259-263

    • ↵3. Sinkins WG, Goel M, Estacion M, and Schilling WP (2004) Association of immunophilins with mammalian TRPC channels. J Biol Chem 279:34521-34529

    • ↵4. Treves S, Franzini-Armstrong C, Moccagatta L, Arnoult C, Grasso C, Schrum A, Ducreux S, Zhu MX, Mikoshiba K, et al. (2004) Junctate is a key element in calcium entry induced by activation of InsP3receptors and/or calcium store depletion. J Cell Biol 166:537-548

    • ↵5. Singh BB, Lockwich TP, Bandyopadhyay BC, Liu X, Bollimuntha S, Brazer SC, Combs C, Das S, Leenders AG, Sheng ZH, et al. (2004) VAMP2-dependent exocytosis regulates plasma membrane insertion of TRPC3 channels and contributes to agonist-stimulated Ca2+ influx. Mol Cell 15:635-646

    • ↵6. Rosker C, Graziani A, Lukas M, Eder P, Zhu MX, Romanin C, and Groschner, K (2004) Ca2+ signaling by TRPC3 involves Na+ entry and local coupling to the Na+/Ca2+ exchanger. J Biol Chem 279:13696-13704

  • TABLE 4

    TRPC4 channel

    Channel name TRPC41,2,3,4,5,6,7,8
    Description TRP receptor-operated channel
    Other names TRP4, CCE1, bCCE
    Molecular information Human unigene: Hs0.262960, chr. 13q13.1-q13.2
    Mouse unigene: Mm0.10100, chr. 3
    Associated subunits Forms homomeric channels in mouse; TRPC1, TRPC5
    Functional assays Patch-clamp, calcium imaging
    Current Nonselective, largely inward, double rectification
    Conductance 41pS; unclear as homomer; estimates range from 18 to 40pS
    Ion selectivity PNa/PCa = 1:1.1,2 1:73
    Activation Activation of Gq-coupled receptors is known to activate TRPC4 current through activation of PLCβ
    Inactivation Not established
    Activators La3+ (100 μM) augments current
    Gating inhibitors None
    Blockers 2-APB, mM La3+, niflumic acid
    Radioligands None
    Channel distribution Brain, testis, placenta, adrenal gland, endothelium
    Physiological functions Mediates agonist-dependent vasorelaxation in vascular endothelium
    Mutations and pathophysiology Impaired agonist-dependent vasorelaxation in TRPC4 –/– mice
    Pharmacological significance Possibly involved in signaling complexes
    Comments Coexpression with TRPC1 or TRPC5 results in a novel NMDA-like voltage-dependent channel

    • chr., chromosome; NMDA, N-methyl-d-aspartate.

    • ↵1. Okada T, Shimizu S, Wakamori M, Maeda A, Kurosaki T, Takada N, Imoto K, and Mori Y (1998) Molecular cloning and functional characterization of a novel receptor-activated TRP Ca2+ channel from mouse brain. J Biol Chem 273:10279-10287

    • ↵2. Schaefer M, Plant TD, Obukhov AG, Hofmann T, Gudermann T, and Schultz G (2000) Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. J Biol Chem 275:17517-17526

    • ↵3. Philipp S, Cavalié A, Freichel M, Wissenbach U, Zimmer S, Trost C, Marquart A, Murakami M, and Flockerzi V (1996) A mammalian capacitative calcium entry channel homologous to Drosophila TRP and TRPL. EMBO J 15:6166-6171

    • ↵4. Freichel M, Suh SH, Pfeifer A, Schweig U, Trost C, Weigerber P, Biel M, Philipp S, Freise D, Droogmans G, et al. (2001) Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4–/– mice. Nat Cell Biol 3:121-127

    • ↵5. Tang Y, Tang J, Chen Z, Trost C, Flockerzi V, Li M, Ramesh V, and Zhu MX (2000) Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF. J Biol Chem 275:37559-37564

    • ↵6. Strübing C, Krapivinsky G, Krapivinsky L, and Clapham DE (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 29:645-655

    • ↵7. Strübing C, Krapivinsky G, Krapivinsky L, and Clapham DE (2003) Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem 278:39014-39019

    • ↵8. Walker RL, Koh SD, Sergeant GP, Sanders KM, and Horowitz B (2002) TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal. Am J Physiol Cell Physiol 283:C1637-C1645

  • TABLE 5

    TRPC5 channel

    Channel name TRPC51,2,3,4,5,6,7
    Description TRP receptor-operated channel
    Other names TRP5, CCE2
    Molecular information Human unigene: Hs0.247868, chr. Xq23
    Mouse unigene: Mm0.328378, chr. X
    Associated subunits Forms heteromultimers with TRPC1 and TRPC4
    Functional assays Patch-clamp, calcium imaging
    Current Nonselective, double rectification
    Conductance ∼38pS as homomer, ∼5pS as TRPC1/C5 heteromer
    Ion selectivity PNa/PCa = 1:9,1 1:1.82
    Activation Stimulation of Gq-coupled receptors, receptor tyrosine kinases
    Inactivation Not established
    Activators Activation of Gq-coupled receptors is known to activate TRPC5 current through activation of PLCγ; La3+ (100 μM) augments current
    Gating inhibitors None
    Blockers mM La3+, 2-APB
    Radioligands None
    Channel distribution Brain, lung, placenta, testis
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Channel properties of heteromeric TRPC1/TRPC4 or TRPC1/TRPC5 are distinct from those of TRPC4 or TPRC5 homomers; rapid insertion of vesicles in growth cones; regulator of neurite morphology

    • chr., chromosome; RTK, receptor tyrosine kinase.

    • ↵1. Okada T, Shimizu S, Wakamori M, Maeda A, Kurosaki T, Takada N, Imoto K, and Mori Y (1998) Molecular cloning and functional characterization of a novel receptor-activated TRP Ca2+ channel from mouse brain. J Biol Chem 273:10279-10287

    • ↵2. Schaefer M, Plant TD, Obukhov AG, Hofmann T, Gudermann T, and Schultz G (2000) Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. J Biol Chem 275:17517-17526

    • ↵3. Strübing C, Krapivinsky G, Krapivinsky L, and Clapham DE (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 29:645-655

    • ↵4. Strübing C, Krapivinsky G, Krapivinsky L, and Clapham DE (2003) Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem 278:39014-39019

    • ↵5. Bezzerides VJ, Ramsey IS, Greka A, Kotecha SA, and Clapham DE (2004) Rapid vesicular translocation and insertion of TRP channels. Nat Cell Biol 6:709-720

    • ↵6. Greka A, Navarro B, Oancea E, Duggan A, and Clapham DE (2003) TRPC5 is a regulator of hippocampal neurite length and growth cone morphology. Nat Neurosci 6:837-845

    • ↵7. Lee YM, Kim BJ, Kim HJ, Yang DK, Zhu MH, Lee KP, So I, and Kim KW (2003) TRPC5 as a candidate for the nonselective cation channel activated by muscarinic stimulation in murine stomach. Am J Physiol Gastrointest Liver Physiol 284:G604-G616

  • TABLE 6

    TRPC6 channel

    Channel name TRPC61,2,3,4,5,6,7
    Description DAG-activated channel
    Other names None
    Molecular information Human unigene: Hs0.159003, chr. 11q21-q22
    Mouse unigene: Mm0.325086, chr. 9
    Associated subunits TRPC3, TRPC7, calmodulin, FKBP12
    Functional assays Patch-clamp, calcium imaging
    Current Inwardly and outwardly rectifying, nonselective cation current
    Conductance 35pS (symmetrical 120 Cs+)
    Ion selectivity PNa/PCa ∼1:5
    Activation Sensitive to intracellular Ca2+
    Inactivation Not established
    Activators DAGs
    Gating inhibitors None
    Blockers 0.25 mM Cd2+, 4 μM La3+, 2 μM Gd2+, 130 μM amiloride, 4 μM SKF96365, 100 μM 2-APB
    Radioligands None
    Channel distribution Lung, heart, brain, muscle
    Physiological functions Cation influx in response to DAG generated by receptor-mediated activation of PLCβ and PLCγ
    Mutations and pathophysiology Not established
    Pharmacological Candidate for receptor-stimulated currents in smooth muscle significance cells
    Comments The DAG response is PKC-independent

    • chr., chromosome.

    • ↵1. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, and Schultz G (1999) Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature (Lond) 397:259-263

    • ↵2. Okada T, Inoue R, Yamazaki K, Maeda A, Kurosaki T, Yamakuni T, Tanaka I, Shimizu S, Ikenaka K, Imoto K, et al. (1999) Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. Ca2+-permeable cation channel that is constitutively activated and enhanced by stimulation of G protein-coupled receptor. J Biol Chem 274:27359-27370

    • ↵3. Inoue R, Okada T, Onoue H, Hara Y, Shimizu S, Naitoh S, Ito Y, and Mori Y (2001) The transient receptor potential protein homologue TRP6 is the essential component of vascular alpha-1 adrenoceptor-activated Ca2+-permeable cation channel. Circ Res 88:325-332

    • ↵4. Corteling RL, Li S, Giddings J, Westwick J, Poll C, and Hall IP (2004) Expression of transient receptor potential C6 and related transient receptor potential family members in human airway smooth muscle and lung tissue. Am J Respir Cell Mol Biol 30:145-154

    • ↵5. Dietrich A, Mederos y Schnitzler M, Emmel J, Kalwa H, Hofmann T, and Gudermann T (2003) N-linked protein glycosylation is a major determinant for basal TRPC3 and TRPC6 channel activity. J Biol Chem 278:47842-47852

    • ↵6. Yu Y, Sweeney M, Zhang S, Platoshyn O, Landsberg J, Rothman A, and Yuan JX (2003) PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am J Physiol Cell Physiol 284:C316-C330

    • ↵7. Shi J, Mori E, Mori Y, Mori M, Li J, Ito Y, and Inoue R (2004) Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cell. J Physiol 561:415-432

  • TABLE 7

    TRPC7 channel

    Channel name TRPC71,2
    Description Cardiac TRP channel
    Other names TRP7
    Molecular information Human unigene: Hs0.283104, chr. 5q31.1
    Mouse unigene: Mm0.62409, chr. 13 B2
    Associated subunits TRPC3, TRPC6, calmodulin, FKBP12
    Functional assays Patch-clamp, calcium imaging
    Current Inwardly and outwardly rectifying, nonselective cation current
    Conductance 50pS (0–100 mV); 25pS (–100 to 0 mV)
    Ion selectivity PNa/PCa ∼1:1.9
    Activation Sensitive to intracellular Ca2+
    Inactivation Not established
    Activators DAG and analogs (100 μM)
    Gating inhibitors None
    Blockers La3+ (100 μM), SKF96365 (25 μM), 0.1–0.4 mM [Ca2+]o
    Radioligands None
    Channel distribution Heart, lung, eye, brain, spleen, testis
    Physiological functions Cation influx in response to Gq activation
    Mutations and pathophysiology Not established
    Pharmacological significance Extracellular ATP (possibly via purinergic receptors), modulated by intracellular calcium, PKC

    • chr., chromosome.

    • ↵1. Okada T, Inoue R, Yamazaki K, Maeda A, Kurosaki T, Yamakuni T, Tanaka I, Shimizu S, Ikenaka K, Imoto K, et al. (1999) Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. Ca2+-permeable cation channel that is constitutively activated and enhanced by stimulation of G protein-coupled receptor. J Biol Chem 274:27359-27370

    • ↵2. Shi J, Mori E, Mori Y, Mori M, Li J, Ito Y, and Inoue R (2004) Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cell. J Physiol 561:415-432

  • TABLE 8

    TRPV1 channel

    Channel name TRPV11,2,3,4,5,6,7,8
    Description Vanilloid (capsaicin) receptor and noxious thermosensor
    Other names VR1, OTRPC1
    Molecular information Human unigene: Hs0.268606, chr. 17p13.3
    Mouse unigene: Mm0.278432, chr. 11 B3
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging, knockout mouse
    Current Outwardly rectifying nonselective current
    Conductance 83pS for heat, 77pS for capsaicin activation measured at positive potentials; Erev in saline solution ∼ 0 mV
    Ion selectivity PNa/PCa = 1:9 for capsaicin-activated current, permeability
    Ca2+ > Mg2+ > Na+ ∼ K+ ∼ Cs+
    PNa/PCa = 1:4 for heat-activated current
    Activation Increasing temperature shifts voltage activation to the physiological range of voltages
    Inactivation cAMP-dependent protein kinase directly phosphorylates TRPV1 to regulate desensitization
    Activators Capsaicin (EC50 = 0.7 μM), resiniferatoxin (EC50 = 40 nM), anandamide, heat (threshold ∼43°C), extracellular protons (indirect sensitization by bradykinin, NGF), ethanol
    Blockers Capsazepine, ruthenium red, iodo-resiniferatoxin, BCTC, PIP2
    Gating inhibitors None
    Radioligands [3H]Resiniferatoxin
    Channel distribution Mainly in trigeminal and dorsal root ganglia, also brain, spinal cord
    Physiological functions Depolarization and calcium entry in response to heat or endogenous agonist, exogenous capsaicin, pain sensation, vasodilation by anandamide
    Mutations and pathophysiology Required for inflammatory thermal hyperalgesia; capsaicin binding site has been determined
    Pharmacological significance Potential target for pain-relieving agents
    Comments TRPV1 is not activated by store depletion

    • chr., chromosome; NGF, nerve growth factor.

    • ↵1. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, and Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature (Lond) 389:816-824

    • ↵2. Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, and Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature (Lond) 411:957-962

    • ↵3. Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, Kanai AJ, Wang E, Ruiz G, De Groat WC, Apodaca G, et al. (2002) Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 5:856-860

    • ↵4. Hu HZ, Gu Q, Wang C, Colton CK, Tang J, Kinoshita-Kawada M, Lee LY, Wood JD, and Zhu MX (2004) 2-Aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2 and TRPV3. J Biol Chem 279:35741-35748

    • ↵5. Woodbury CJ, Zwick M, Wang S, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, and Davis BM (2004) Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci 24:6410-6415

    • ↵6. Zhuang ZY, Xu H, Clapham DE, and Ji RR (2004) Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization. J Neurosci 24:8300-8309

    • ↵7. Bhave G, Zhu W, Wang H, Brasier DJ, Oxford GS, and Gereau RW 4th (2002) cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron 15:721-731

    • ↵8. Trevisani M, Gazzieri D, Benvenuti F, Campi B, Dinh QT, Groneberg DA, Rigoni M, Emonds-Alt X, Creminon C, Fischer A, et al. (2004) Ethanol causes inflammation in the airways by a neurogenic and TRPV1-dependent mechanism. J Pharmacol Exp Ther 309:1167-1173

  • TABLE 9

    TRPV2 channel

    Channel name TRPV21,2,3,4,5,6
    Description Noxious heat thermosensor channel
    Other names VRL-1, GRC, OTRPC2
    Molecular information Human unigene: Hs0.279746, chr. 17p11.2
    Mouse unigene: Mm0.288064, chr. 11 B2
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Outwardly rectifying nonselective cation current
    Conductance Erev in saline solution ∼0 mV
    Ion selectivity PNa/PCa = 1:3
    Ca2+ > Mg2+ > Na+, K+, Cs+
    Activation High temperature (>52°C), PKA modulation of surface expression
    Inactivation Not established
    Activators Heat (threshold = 52°C), IGF-I
    Gating inhibitors None
    Blockers Ruthenium red, La3+, SKF96365
    Radioligands None
    Channel distribution Mainly dorsal root ganglion neurons, brain, spinal cord, spleen, and lung
    Physiological functions Calcium entry in thermal pain sensation
    Mutations and pathophysiology Not established
    Pharmacological significance Potential target for pain-relieving agents
    Comments Insensitive to capsaicin

    • chr., chromosome; PKA, protein kinase A; IGF-I, insulin-like growth factor-I.

    • ↵1. Caterina MJ, Rosen TA, Tominaga M, Brake AJ, and Julius D (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature (Lond) 398:436-441

    • ↵2. Hu HZ, Gu Q, Wang C, Colton CK, Tang J, Kinoshita-Kawada M, Lee LY, Wood JD, and Zhu MX (2004) 2-Aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2 and TRPV3. J Biol Chem 279:35741-35748

    • ↵3. Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, Shigekawa M, and Imaizumi Y (2003) TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ Res 93:829-838

    • ↵4. Stokes AJ, Shimoda LM, Koblan-Huberson M, Adra CN, and Turner H (2004) A TRPV2-PKA signaling module for transduction of physical stimuli in mast cells. J Exp Med 200:137-147

    • ↵5. Woodbury CJ, Zwick M, Wang S, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, and Davis BM (2004) Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci 24:6410-6415

    • ↵6. Stokes AJ, Wakano C, Del Carmen KA, Koblan-Huberson M, and Turner HJ (2005) Formation of a physiological complex between TRPV2 and RGA protein promotes cell surface expression of TRPV2. J Cell Biochem 94:669-683

  • TABLE 10

    TRPV3 channel

    Channel name TRPV31,2,3,4,5
    Description Warmth sensor channel
    Other names None
    Molecular information Human unigene: Hs0.446255, chr. 17p13.2
    Mouse unigene: Mm0.347652, chr. 11 B4
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Outwardly rectifying nonselective cation current
    Conductance 170pS
    Ion selectivity PNa/PCa = 0.08
    Activation ∼35°C
    Inactivation Cooling
    Activators Increasing temperature
    Gating inhibitors None
    Blockers Ruthenium red
    Radioligands None
    Channel distribution Brain (cortex, thalamus), skin, hair follicles, tongue, stomach, spinal cord, superior cervical ganglion, dorsal root ganglion, trigeminal ganglion
    Physiological functions Putative, warm sensation
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Like TRPV1 and TRPV2, TRPV3 exhibits sensitivity to temperature changes; unique features are hysteresis behavior on heating and cooling and sensitization

    • chr., chromosome.

    • ↵1. Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P, Bevan S, and Patapoutian A (2002) A heat sensitive TRP channel expressed in keratinocytes. Science (Wash DC) 296:2046-2049

    • ↵2. Xu H, Ramsey, I. Kotecha SA, Moran, M. 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 (Lond) 418:181-186

    • ↵3. 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 (Lond) 418:186-190

    • ↵4. Chung MK, Lee H, Mizuno A, Suzuki M, and Caterina M (2004a) TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J Biol Chem 279:21569-21575

    • ↵5. Hu HZ, Gu Q, Wang C, Colton CK, Tang J, Kinoshita-Kawada M, Lee LY, Wood JD, and Zhu MX (2004) 2-Aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2 and TRPV3. J Biol Chem 279:35741-35748

  • TABLE 11

    TRPV4 channel

    Channel name TRPV41,2,3,4,5,6,7,8,9,10,11
    Description Osmosensor channel
    Other names OTRPC4, VR-OAC, VRL-2, TRP-12
    Molecular information Human unigene: Hs0.506713, chr. 12q24.1
    Mouse unigene: Mm0.266450, chr. 5
    Associated subunits Calmodulin
    Functional assays Patch-clamp, calcium imaging
    Current Outwardly rectifying, nonselective current
    Conductance 90pS
    Ion selectivity PNa/PCa = 1:6
    Activation Osmolarity (EC50 = 270 mOsmol/l), phorbol esters, arachidonic acid, EETs, stretch
    Inactivation Calmodulin/Ca2+
    Activators Reduced osmolarity (see “Comments”)
    Gating inhibitors None
    Blockers Ruthenium red, gadolinium, lanthanum
    Radioligands None
    Channel distribution Brain, liver, kidney, fat, heart, testis, salivary gland, trachea
    Physiological functions Osmolarity sensing with thermal modulation
    Mutations and pathophysiology Deletion of the ankyrin repeat domain blunts the response to low osmolarity solutions
    Pharmacological significance Not established
    Comments TRPV4 is not activated by store depletion

    • chr., chromosome; VR-OAC, vanilloid receptor-related osmotically activated channel; EET, eicosatetraenoic acid.

    • ↵1. Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, and Plant TD (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol 2:695-702

    • ↵2. Denis CS, Sali A, Hudspeth AJ, Friedman JM, and Heller S (2000) Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103:525-535

    • ↵3. Mizuno A, Matsumoto N, Imai M, and Suzuki M (2003) Impaired osmotic sensation in mice lacking TRPV4. Am J Physiol Cell Physiol 285:C96-C101

    • ↵4. Liedtke W, Tobin DM, Bargmann CI, and Friedman JM (2003) Mammalian TRPV4 (VR-OAC) directs behavioral responses to osmotic and mechanical stimuli in Caenorhabditis elegans. Proc Natl Acad Sci USA 100 (Suppl 2):14531-14536

    • ↵5. Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, and Nilius B (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature (Lond) 424:434-438

    • ↵6. Chung MK, Lee H, Mizuno A, Suzuki M, and Caterina M (2004a) TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J Biol Chem 279:21569-21575

    • ↵7. Jia Y, Wang X, Varty L, Rizzo CA, Yang R, Correll CC, Phelps PT, Egan RW, and Hey JA (2004) Functional TRPV4 channels are expressed in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 287:L272-L278

    • ↵8. Suzuki M, Watanabe Y, Oyama Y, Mizuno A, Kusano E, Hirao A, and Ookawara S (2003) Localization of mechanosensitive channel TRPV4 in mouse skin. Neurosci Lett 353:189-192

    • ↵9. Tian W, Salanova M, Xu H, Lindsley JN, Oyama TT, Anderson S, Bachmann S, and Cohen DM (2004) Renal expression of osmotically responsive cation channel TRPV4 is restricted to water-impermeant nephron segments. Am J Physiol Renal Physiol 287:F17-F24

    • ↵10. Strotmann R, Schultz G, and Plant TD (2003) Ca2+-dependent potentiation of the nonselective cation channel TRPV4 is mediated by a C-terminal calmodulin binding site. J Biol Chem. 278:26541-26549

    • ↵11. Vriens J, Watanabe H, Janssens A, Droogmans G, Voets T, and Nilius B (2003) Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4. Proc Natl Acad Sci USA 101:396-401

  • TABLE 12

    TRPV5 channel

    Channel name TRPV51,2,3,4,5
    Description Calcium-selective TRP channel
    Other names ECaC1, CaT2
    Molecular information Human unigene: Hs0.283369, chr. 7q35
    Mouse unigene: Mm0.135734, chr. 6 B1
    Associated subunits NHERF, S100 protein, TRPV6
    Functional assays Patch-clamp, calcium imaging
    Current Inwardly rectifying, calcium-sensitive cation channel
    Conductance 75pS in calcium-free solution
    Erev in saline solution >50 mV
    Ion selectivity Ca2+ > Ba2+ > Sr2+ > Mn2+; PNa/PCa = 1:107
    Activation Mechanism not established, constitutively active
    Inactivation Not established
    Activators None
    Gating inhibitors None
    Blockers Ruthenium red (100 nM), La3+
    Radioligands None
    Channel distribution Intestine, kidney, placenta
    Physiological functions Not established
    Mutations and pathophysiology D542 is crucial for calcium sensitivity
    Pharmacological significance Not established
    Comments One of only two known TRP channels (with TRPV6) that is relatively highly Ca2+-selective

    • chr., chromosome; NHERF, Na+/H+ exchange regulatory factor.

    • ↵1. Vennekens R, Hoenderop GJ, Prenen J, Stuiver M, Willems PHGM, Droogmans G, Nilius B, and Bindels RJM (2000) Permeation and gating properties of the novel epithelial Ca2+ channel. J Biol Chem 275:3963-3969

    • ↵2. Nilius B, Vennekens R, Prenen J, Hoenderop JG, Bindels RJ, and Droogmans G (2000) Whole-cell and single channel monovalent cation currents through the novel rabbit epithelial Ca2+ channel ECaC. J Physiol 527 (Pt 2):239-248

    • ↵3. Hoenderop JGJ, van der Kemp AWCM, Hartog A, van de Graaf SFJ, van Os CH, Willems PHGM, and Bindels RJM (1999) Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem 274:8375-8378

    • ↵4. van de Graaf SF, Hoenderop JG, Gkika D, Lamers D, Prenen J, Rescher U, Gerke V, Staub O, Nilius B, and Bindels RJ (2003) Functional expression of the epithelial Ca2+ channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex. EMBO J 22:1478-1487

    • ↵5. Embark HM, Setiawan I, Poppendieck S, van de Graaf SF, Boehmer C, Palmada M, Wieder T, Gerstberger R, Cohen P, Yun CC, et al. (2004) Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. Cell Physiol Biochem 14:203-212

  • TABLE 13

    TRPV6 channel

    Channel name TRPV61,2,3
    Description Calcium-selective TRP channel
    Other names ECaC2, CaT1
    Molecular information Human unigene: Hs0.302740, chr. 7q33–34
    Mouse unigene: Mm0.296889, chr. 6
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Inwardly rectifying, calcium-sensitive cation current
    Conductance 42–58pS in calcium-free solution
    Erev in saline solution >50 mV
    Ion selectivity Ca2+ > Ba2+ > Sr2+ > Mn2+; PNa/PCa = 1:130
    Activation Constitutively active
    Inactivation Not established
    Activators None
    Gating inhibitors None
    Blockers Ruthenium red (5 μM), La3+
    Radioligands None
    Channel distribution Kidney, intestine
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments One of only two known TRP channels (with TRPV5) that is relatively highly Ca2+-selective

    • chr., chromosome.

    • ↵1. Yue L, Peng JB, Hediger MA, and Clapham DE (2001) CaT1 manifests the pore properties of the calcium-release-activated calcium channel. Nature (Lond) 410:705-709

    • ↵2. Bodding M and Flockerzi V (2004) Ca2+ dependence of the Ca2+-selective TRPV6 channel. J Biol Chem 279:36546-36552

    • ↵3. Lambers TT, Weidema AF, Nilius B, Hoenderop JG, and Bindels RJ (2004) Regulation of the mouse epithelial Ca2+ channel TRPV6 by the Ca2+-sensor calmodulin. J Biol Chem 279:28855-28861

  • TABLE 14

    TRPM1 channel

    Channel name TRPM11,2,3,4
    Description Putative melastatin TRP channel
    Other names Melastatin, LTRPC1
    Molecular information Human unigene: Hs0.155942, chr. 15q13-q14
    Mouse unigene: Mm0.38875, chr. 7
    Associated subunits Short transcript of M1 (MLSN-S)
    Functional assays Calcium imaging
    Current Not established
    Conductance Not established
    Ion selectivity Ca2+ permeable
    Activation Not established
    Inactivation Not established
    Activators None
    Blockers None
    Gating inhibitors None
    Radioligands None
    Channel distribution Eye, melanocytes
    Physiological functions Not established
    Mutations and pathophysiology Down-regulated in melanoma
    Pharmacological significance Alternatively spliced form suppresses calcium entry though HEK cells expressing full-length melastatin
    Comments TRPM1 is the founding member of the TRPM family; alternatively spliced long and short forms exist; the two forms interact

    • chr., chromosome; HEK, human embryonic kidney.

    • ↵1. Hunter JJ, Shao J, Smutko JS, Dussault BJ, Nagle DL, Woolf EA, Holmgren LM, Moore KJ, and Shyjan AW (1998) Chromosomal localization and genomic characterization of the mouse melastatin gene (Mlsn1). Genomics 54:116-123

    • ↵2. Duncan LM, Deeds J, Cronin FE, Donovan M, Sober AJ, Kauffman M, and McCarthy JJ (2001) Melastatin expression and prognosis in cutaneous malignant melanoma. J Clin Oncol 19:568-576

    • ↵3. Fang D and Setaluri V (2000) Expression and up-regulation of alternatively spliced transcripts of melastatin, a melanoma metastasis-related gene, in human melanoma cells. Biochem Biophys Res Commun 279:53-61

    • ↵4. Xu XZ, Moebius F, Gill DL, and Montell C (2001) Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform. Proc Natl Acad Sci USA 98:10692-10697

  • TABLE 15

    TRPM2 channel

    Channel name TRPM21,2,3,4,5,6,7
    Description Nucleotide-sensing TRP channel
    Other names TRPC7, LTRPC2
    Molecular information Human unigene: Hs0.369759, chr. 21q22.3
    Mouse unigene: Mm0.276762, chr. 10 C1
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Weakly voltage-sensitive cation current
    Conductance 60pS, 58pS (negative potentials); 76pS at positive potentials
    H2O2-induced channel (52.3pS), β-NAD+-activated channel (59pS)
    Ion selectivity Nonselective, permeant to Na+, Ca2+, and K+
    Activation Redox sensor, activation by H2O2 and TNF-α; modulated by arachidonic acid
    Inactivation Flufenamic acid, clotrimazole, econazole, PARP inhibitors
    Activators ADP-ribose, β-NAD+, increased [Ca2+]i potentiates (EC50 = 340 nM)
    Gating inhibitors None
    Blockers None
    Radioligands None
    Channel distribution Brain, placenta, lung, spinal cord, spleen, lymphocytes
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established

    • chr., chromosome; NAD, nicotinamide adenine dinucleotide; TNF, tumor necrosis factor; PARP, poly(ADP-ribose) polymerase.

    • ↵1. Nagamine K, Kudoh J, Minoshima S, Kawasaki K, Asakawa S, Ito F, and Shimizu N (1998) Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics 54:124-131

    • ↵2. Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, Schmitz C, Stokes AJ, Zhu Q, Bessman MJ, Penner R, et al. (2001) ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature (Lond) 411:595-599

    • ↵3. Sano Y, Inamura K, Miyake A, Mochizuki S, Yokoi H, Matsushime H, and Furuichi K (2001) Immunocyte Ca2+ influx system mediated by LTRPC2. Science (Wash DC) 293:1327-1330

    • ↵4. Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S, Mori E, Kudoh J, et al. (2002) LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 9:163-173

    • ↵5. Hill K, McNulty S, and Randall AD (2004) Inhibition of TRPM2 channels by the antifungal agents clotrimazole and econazole. Naunyn Schmiedeberg's Arch Pharmacol 370:227-237

    • ↵6. Fonfria E, Marshall IC, Benham CD, Boyfield I, Brown JD, Hill K, Hughes JP, Skaper SD, and McNulty S (2004) TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br J Pharmacol 143:186-192

    • ↵7. Kraft R, Grimm C, Grosse K, Hoffmann A, Sauerbruch S, Kettenmann H, Schultz G, Harteneck C (2004) Hydrogen peroxide, and ADP-ribose induce TRPM2-mediated calcium influx and cation currents in microglia. Am J Physiol Cell Physiol 286:C129-C137

  • TABLE 16

    TRPM3 channel

    Channel name TRPM31,2,3
    Description Melastatin-related channel
    Other names hKIAA1616, LTRPC3
    Molecular information Human unigene: Hs0.47288, chr. 9q21.11
    Mouse unigene: Mm0.124567, chr. 19 B
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current near linear I–V
    Conductance 83pS (140 mM symmetrical Na)
    Ion selectivity PNa/PCa ∼0.6 nonselective cationic
    Activation Constitutive, enhanced by hypo-osmolarity, sphingolipids
    Inactivation Independent of [Ca2+]i
    Activators Sphingolipids
    Gating inhibitors None
    Blockers Gd3+ (100 μM), insensitive to ruthenium red (1 μM)
    Radioligands None
    Channel distribution Widely expressed, kidney, brain
    Physiological functions Ca2+ absorption in renal collecting tubule
    Mutations and pathophysiology Not established
    Pharmacological significance Not established

    • chr., chromosome.

    • ↵1. Grimm C, Kraft R, Sauerbruch S, Schultz G, and Harteneck C (2003) Molecular and functional characterization of the melastatin-related cation channel TRPM3. J Biol Chem 278:21493-21501

    • ↵2. Lee N, Chen J, Sun L, Wu S, Gray KR, Rich A, Huang M, Lin JH, Feder JN, Janovitz EB, et al. (2003) Expression and characterization of human transient receptor potential melastatin 3 (hTRPM3) J Biol Chem 278:20890-20897

    • ↵3. Grimm C, Kraft R, Schultz G, and Harteneck C (2004) Activation of the melastatin-related cation channel TRPM3 by d-erythro-sphingosine. Mol Pharmacol 67:798-805

  • TABLE 17

    TRPM4 channel

    Channel name TRPM41,2,3,4,5
    Description Ca2+-activated Na+ channel
    Other names FLJ20041, LTRPC4, TRPM4b
    Molecular information Human unigene: Hs0.467101, chr. 19q13.33
    Mouse unigene: Mm0.349430, chr. 7 B3
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Steep outward rectification >0 mV; instantaneous I–V linear
    Conductance 25pS (isotonic monovalent)
    Ion selectivity PNa/PCa ∼100 (M4b)
    Activation Kact: 300–500 nM [Ca2+]i; >1 μM
    Inactivation Not established (Ca2+-regulated)
    Activators [Ca2+]i
    Gating inhibitors None
    Blockers M4a: 80 μM La3+, Gd3+
    M4b: intracellular free ATP4-, 1.7 μM, spermine, ADP
    Radioligands None
    Channel distribution Probably ubiquitous
    Physiological functions Regulation of calcium oscillations in activated T lymphocytes
    Myogenic cerebral artery constriction
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments VMCA is an unusual feature; decavanadate (2 μM) inhibits voltage dependence

    • chr., chromosome; VMCA, voltage-modulated calcium-activated.

    • ↵1. Launay P, Fleig A, Perraud AL, Scharenberg AM, Penner R, and Kinet JP (2002) TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell 109:397-407

    • ↵2. Nilius B, Prenen J, Droogmans G, Voets T, Vennekens R, Freichel M, Wissenbach U, and Flockerzi V (2003) Voltage dependence of the Ca2+-activated cation channel TRPM4. J Biol Chem 278:30813-30820

    • ↵3. Earley S, Waldron BJ, and Brayden JE (2004) Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ Res 95:922-929

    • ↵4. Launay P, Cheng H, Srivatsan S, Penner R, Fleig A, and Kinet JP (2004) TRPM4 regulates calcium oscillations after T cell activation. Science (Wash DC) 306:1374-1377

    • ↵5. Nilius B, Prenen J, Voets T, and Droogmans G (2004) Intracellular nucleotides and polyamines inhibit the Ca2+-activated cation channel TRPM4b. Pflugers Arch Eur J Physiol 448:70-75

  • TABLE 18

    TRPM5 channel

    Channel name TRPM51,2,3
    Description Nonselective, monovalent cation channel
    Other names Mtr1, LTRPC5
    Molecular information Human unigene: Hs0.272287, chr. 11p15.5
    Mouse unigene: Mm0.286668, chr. 7 F5
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Steep outward rectification >0 mV
    Conductance 23pS (isotonic monovalent)
    Ion selectivity PNa/PCa = >20 (monovalent selective)
    Activation GPCR (T1R, T2R), Ggus-PLCβ2 [Ca2+]i 1—100 μM
    Inactivation Not established
    Activators [Ca2+]i
    Gating inhibitors None
    Blockers Not established
    Radioligands None
    Channel distribution Widely distributed, eye, liver, lung, tongue, stomach
    Physiological functions Sweet, bitter, umami taste transduction
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments VMCA is an unusual feature; candidate gene for rhabdomyosarcomas, Wilms' tumor, and Beckwith-Wiedemann syndrome

    • chr., chromosome; GPCR, G protein-coupled receptor; VMCA, voltage-modulated calcium-activated.

    • ↵1. Hofmann T, Chubanov V, Gudermann T, and Montell C (2003) TRPM5 is a voltage-modulated and Ca2+-activated monovalent selective cation channel. Curr Biol 13:1153-1158

    • ↵2. Liu D and Liman ER (2003) Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5. Proc Natl Acad Sci USA 100:15160-15165

    • ↵3. Prawitt D, Monteilh-Zoller MK, Brixel L, Spangenberg C, Zabel B, Fleig A, and Penner R (2003) TRPM5 is a transient Ca2+-activated cation channel responding to rapid changes in [Ca2+]i. Proc Natl Acad Sci USA 100:15166-15171

  • TABLE 19

    TRPM6 channel

    Channel name TRPM61,2,3,4
    Description Channel-kinase TRP channel
    Other names ChaK2
    Molecular information Human unigene: Hs0.272225, chr. 9q21.13
    Mouse unigene: Mm0.215171, chr. 19 B
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Steeply outward rectifying >0 mV
    Conductance Not established
    Ion selectivity Nonselective cationic, Mg2+ permeant
    Activation Not established
    Inactivation Not established
    Activators None
    Gating inhibitors None
    Blockers Ruthenium red
    Radioligands None
    Channel distribution Widely distributed, kidney, gastrointestinal tract
    Physiological functions Renal and gastrointestinal Mg2+ uptake
    Mutations and pathophysiology Human hypomagnesemia with secondary hypocalcemia (HGH)
    Pharmacological significance Not established
    Comments Contains a protein kinase on its C terminus as part of the protein (chanzyme); currently difficult to separate from TRPM7 current

    • chr., chromosome.

    • ↵1. Ryazanova LV, Pavur KS, Petrov N, Dorovkov MV, and Ryazanov AG (2001) Novel type of signaling molecules: protein kinases covalently linked with ion channels. Mol Biol 35:271-283

    • ↵2. 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 31:166-170

    • ↵3. 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 31:171-174

    • ↵4. Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, and Hoenderop JG (2004) TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279:19-25

  • TABLE 20

    TRPM7 channel

    Channel name TRPM71,2,3,4,5,6,7
    Description Kinase TRP channel
    Other names TRP-PLIK, LTRPC7, ChaK(1)
    Molecular information Human unigene: Hs0.512894, chr. 15q21
    Mouse unigene: Mm0.215171, chr. 2 F2
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Weakly voltage-sensitive cation current
    Conductance 105pS
    Ion selectivity PNa/PCa = 3:1 in outward direction; Na+, Ca2+, Mg2+ inward
    Activation Not established
    Inactivation Activation of receptors coupled to PLC hydrolyzes PIP2 to inactivate the channel
    Activators PIP2
    Gating inhibitors None
    Blockers Mg2+ (EC50 ∼ 0.6 mM), La3+, polyamines
    Radioligands None
    Channel distribution Ubiquitous
    Physiological functions Cellular Mg2+ homeostasis proposed; potential for other trace metals, such as Zn2+, Mn2+; oxygen-glucose deprivation-induced calcium influx and neuronal death
    Mutations and pathophysiology Lethal in DT-40 cell line
    Pharmacological significance Not established
    Comments TRPM7 is a bifunctional protein with both ion channel and kinase activities; the protein autophosphorylates, but no other substrates are known

    • chr., chromosome.

    • ↵1. Runnels LW, Yue L, and Clapham DE (2002) The TRPM7 channel is inactivated by PIP2 hydrolysis. Nat Cell Biol 4:329-336

    • ↵2. Runnels LW, Yue L, and Clapham DE (2001) TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science (Wash DC) 291:1043-1047

    • ↵3. 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 (Lond) 411:590-595

    • ↵4. Ryazanova LV, Pavur KS, Petrov N, Dorovkov MV, and Ryazanov AG (2001) Novel type of signaling molecules: protein kinases covalently linked with ion channels. Mol Biol 35:271-283

    • ↵5. Yamaguchi H, Matsushita M, Nairn AC, and Kuriyan J (2001) Crystal structure of the atypical protein kinase domain of a TRP channel with phosphotransferase activity. Mol Cell 7:1047-1057

    • ↵6. Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, and Tymianski M (2003) A key role for TRPM7 channels in anoxic neuronal death. Cell 115:863-877

    • ↵7. Kerschbaum HH, Kozak JA, and Cahalan MD (2003) Polyvalent cations as permeant probes of MIC and TRPM7 pores. Biophys J 84:2293-2305

  • TABLE 21

    TRPM8 channel

    Channel name TRPM81,2,3,4,5
    Description Cooling and menthol-sensing TRP channel
    Other names CMR1 (cold and menthol receptor), Trp-p8
    Molecular information Human unigene: Hs0.366053, chr. 2q37.1
    Mouse unigene: Mm0.218753, chr. 1 D
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Steeply outwardly rectifying >0 mV
    Conductance 83pS (slope conductance)
    Ion selectivity PNa/PCa = 0.3, nonselective cation channel
    Activation 8–26°C
    Inactivation Warming >28°C
    Activators Cooling below 22–26°C, cooling agents such as menthol (EC50 = 70 μM) and icilin (EC50 = 360 nM); less potent: linalool, geraniol, hydroxycitronella
    Gating inhibitors None
    Blockers BCTC, thio-BCTC, capsazepine
    Radioligands None
    Channel distribution Small sensory neurons of trigeminal ganglion and dorsal root ganglia, prostate epithelium
    Physiological functions Cold sensation
    Mutations and pathophysiology Not established
    Pharmacological significance Putative menthol receptor
    Comments The neuronal colocalization and potential coassembly of TRPV1, TRPV2, TRPV3, and TRPM8 are under study

    • chr., chromosome.

    • ↵1. McKemy DD, Neuhausser WM, and Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature (Lond) 416:52-58

    • ↵2. Peir 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 108:705-715

    • ↵3. Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, and Nilius B (2004) The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature (Lond) 430:748-754

    • ↵4. Brauchi S, Orio P, and Latorre R (2004) Clues to understanding cold sensation: thermodynamics and electrophysiological analysis of the cold receptor TRPM8. Proc Natl Acad Sci USA 101:15494-15499

    • ↵5. Behrendt HJ, Germann T, Gillen C, Hatt H, and Jostock R (2004) Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br J Pharmacol 141:737-745

  • TABLE 22

    TRPA1 channel

    Channel name TRPA11,2,3
    Description Nonselective cation channel subunit
    Other names ANKTM1 (ankyrin transmembrane protein 1)
    Molecular information Human unigene: Hs0.137674, chr. 8q13
    Mouse unigene: Mm0.186329, chr. 1 A3
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Moderately outward rectifying >0 mV
    Conductance Not established
    Ion selectivity PNa/PCa ∼0.7
    Activation Mustard oils, PLC-coupled GPCRs, icilin, cannabinoids, cold?, mechanosensation?
    Inactivation Not established
    Activators Icilin (100 μM)
    Gating inhibitors None
    Blockers Ruthenium red (5 μM)
    Radioligands None
    Channel distribution Expressed in sensory neurons of trigeminal and dorsal root ganglia; ear
    Physiological functions Sensitive to plant-derived irritants such as mustard oils and perhaps to membrane/cytoskeletal perturbations such as stretch (as the hearing transduction channel); may depolarize nociceptors in response to pro-algesic agents (e.g. bradykinin, serotonin, and histamine) that activate PLC-coupled receptors; originally proposed to sense painfully cold temperatures
    Mutations and pathophysiology Not established
    Pharmacological significance Putative wasabi receptor
    Comments Expressed by a subset of TRPV1-expressing sensory neurons
    Decreased in fibroblasts after oncogenic transformation

    • chr., chromosome; GPCR, G protein-coupled receptor.

    • ↵1. 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 112:819-829

    • ↵2. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, and Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature (Lond) 427:260-265

    • ↵3. Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung EL, Derfler BH, Duggan A, et al. (2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature (Lond) 432:723-730

  • TABLE 23

    TRPP1 channel

    Channel name TRPP11,2,3,4,5
    Description Nonselective cation channel subunit
    Other names PC2, PKD2, TRPP2
    Molecular information Human unigene: Hs0.181272, chr. 4q21–23
    Mouse unigene: Mm0.6442, chr. 5
    Associated subunits PKD1, Hax-1, cortactin, tropomyosin, actin cadherin via PKD1
    Functional assays Patch-clamp, calcium imaging
    Current Near linear when coexpressed with PKD1
    Conductance 40pS in high [Ca2+]4, ∼50pS in symmetrical 140 mM K+5
    Ion selectivity PNa/PCa ∼0.7
    Activation Mechanical stress?
    Inactivation Not established
    Gating inhibitors None
    Blockers Amiloride (30 μM), Gd3+, La3+
    Radioligands None
    Channel distribution Widely expressed; kidney, pancreas, heart, testis, blood
    Physiological functions Mouse cardiac, skeletal, and renal development; kidney and liver cyst formation, with PC2 (PKD2) mechanosensation in cilia (kidney)
    Mutations and pathophysiology Not established
    Comments Homomeric vs. heteromeric (with PKD1) channel function not clear; note that the nomenclature is not settled by HUGO–here we have grouped only the 6TM subtypes as TRPPs and left the longer (11TMs such as PKD1) polycystins out of the classification

    • chr., chromosome; PC2, polycystin-2; PKD2, polycystic kidney disease protein 2; PKD1, polycystin-1.

    • ↵1. Wu G, D'Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou H Jr, Kucherlapati R, et al. (1998) Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93:177-188

    • ↵2. Delmas P (2004) Polycystins: from mechanosensation to gene regulation. Cell 118:145-148

    • ↵3. Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, and Sukhatme VP (1999) Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci USA 96:3934-3939

    • ↵4. Gonzalez-Perret S, Kim K, Ibarra C, Damiano AE, Zotta E, Batelli M, Harris PC, Reisin IL, Arnaout MA, and Cantiello HF (2001) Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc Natl Acad Sci USA 98:1182-1187

    • ↵5. Luo Y, Vassilev PM, Li X, Kawanabe Y, and Zhou J (2003) Native polycystin 2 functions as a plasma membrane Ca2+-permeablecation channel in renal epithelia. Mol Cell Biol 23:2600-2607

  • TABLE 24

    TRPP2 channel

    Channel name TRPP21
    Description Nonselective cation channel subunit
    Other names PKD2L1, TRPP3
    Molecular information Human unigene: Hs0.159241, chr. 10q24
    Mouse unigene: Mm.308481
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Near linear
    Conductance 137pS in 100 mM Na+
    Ion selectivity PNa/PCa ∼ 1:4
    Inactivation Not established
    Activators 1 μM [Ca2+]i
    Gating inhibitors None
    Blockers Not established
    Radioligands None
    Channel distribution Eye, kidney, testis
    Physiological functions Involved in kidney and retinal development based on krd (P3–/–mouse)
    Mutations and pathophysiology Not established
    Comments Electrophysiological properties not firmly established; note that the nomenclature is not settled by HUGO—here we have grouped only the 6TM subtypes as TRPPs and left the longer (11TMs such as PKD1) polycystins out of the classification

    • chr., chromosome; PKD2L1, polycystic kidney disease protein 2-like protein 1.

    • ↵1. Nomura H, Turco AE, Pei Y, Kalaydjieva L, Schiavello T, Weremowicz S, Ji W, Morton CC, Meisler M, Reeders ST, et al. (1998) Identification of PKDL, a novel polycystic kidney disease 2-like gene whose murine homologue is deleted in mice with kidney and retinal defects. J Biol Chem 273:25967-25973

  • TABLE 25

    TRPP3 channel

    Channel name TRPP31
    Description Nonselective cation channel subunit
    Other names PKD2L2, TRPP5
    Molecular information Human unigene: Hs0.546413, chr. 19p13.3-p13.2
    Mouse unigene: Mm0.8356, chr. 8
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Not established
    Conductance 83pS in 100 mM Na+
    Ion selectivity PNa/PCa ∼ 1
    Activation Not established
    Inactivation Not established
    Activators [Ca2+]i?
    Gating inhibitors Not established
    Blockers Not established
    Radioligands Not established
    Channel distribution Near ubiquitous
    Physiological functions Role in sorting/transport in late endocytic pathway; defective in mucolipidosis type IV lysosomal storage disease
    Mutations and pathophysiology Not established
    Comments Electrophysiological properties not firmly established; note that the nomenclature is not settled by HUGO—here we have grouped only the 6TM subtypes as TRPPs and left the longer (11TMs such as PKD1) polycystins out of the classification

    • chr., chromosome; PKD2L2, polycystic kidney disease protein 2-like protein 2.

    • ↵1. Guo L, Schreiber TH, Weremowicz S, Morton CC, Lee C, and Zhou J (2000) Identification and characterization of a novel polycystin family member, polycystin-L2, in mouse and human: sequence, expression, alternative splicing, and chromosomal localization. Genomics 64:241-251

  • TABLE 26

    TRPML1 channel

    Channel name TRPML11,2
    Description Nonselective cation channel subunit
    Other names MCOLN1, mucolipin 1
    Molecular information Human unigene: Hs0.310431, chr. 5q31
    Mouse unigene: Mm0.226899, chr. 18 C
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Not established
    Conductance 300pS?
    Ion selectivity PNa/PCa ∼1
    Activation Not established
    Inactivation Not established
    Activators [Ca2+]i?
    Gating inhibitors Not established
    Blockers Amiloride (130 μM), Gd3+, La3+, Ni2+
    Radioligands Not established
    Channel distribution Widely expressed, heart kidney, testis, blood
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Comments Electrophysiological properties not firmly established

    • chr., chromosome.

    • ↵1. LaPlante JM, Falardeau J, Sun M, KanazirskaM, Brown EM, Slaugenhaupt SA, and Vassilev PM (2002) Identification and characterization of the single channel function of human mucolipin-1 implicated in mucolipidosis type IV, a disorder affecting the lysosomal pathway. FEBS Lett 532:183-187

    • ↵2. LaPlante JM, Ye CP, Quinn SJ, Goldin E, Brown EM, Slaugenhaupt SA, and Vassilev PM (2004) Functional links between mucolipin-1 and Ca2+-dependent membrane trafficking in mucolipidosis IV. Biochem Biophys Res Commun 322:1384-1391

  • TABLE 27

    TRPML2 channel

    Channel name TRPML21
    Description Nonselective cation channel subunit
    Other names MCOLN2, mucolipin 2
    Molecular information Human unigene: Hs0.459526, chr. 1p22
    Mouse unigene: Mm0.116862, chr. 3
    Associated subunits Not established
    Functional assays Not established
    Current Not established
    Conductance Not established
    Ion selectivity Not established
    Activation Not established
    Inactivation Not established
    Activators Not established
    Gating inhibitors Not established
    Blockers Not established
    Radioligands Not established
    Channel distribution Widely expressed
    Physiological functions Not established
    Mutations and pathophysiology Not established

    • chr., chromosome.

    • ↵1. Di Palma F, Belyantseva IA, Kim HJ, Vogt TF, Kachar B, and Noben-Trauth K (2002) Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice. Proc Natl Acad Sci USA 99:14994-14999

  • TABLE 28

    TRPML3 channel

    Channel name TRPML31
    Description Nonselective cation channel subunit
    Other names MCOLN3, mucolipin 3
    Molecular information Human unigene: Hs0.535239, chr. 1p22.3
    Mouse unigene: Mm0.114683, chr. 3
    Associated subunits Not established
    Functional assays Patch-clamp, calcium imaging
    Current Not established
    Conductance Not established
    Ion selectivity Not established
    Activation Not established
    Inactivation Not established
    Activators Not established
    Gating inhibitors Not established
    Blockers Not established
    Radioligands Not established
    Channel distribution Widely expressed
    Physiological functions Hair cell, stereocilia maturation
    Mutations and pathophysiology Not established
    Comments Va

    • chr., chromosome; Va, Varitint-waddler mouse.

    • ↵1. Di Palma F, Belyantseva IA, Kim HJ, Vogt TF, Kachar B, and Noben-Trauth K (2002) Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice. Proc Natl Acad Sci USA 99:14994-14999

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OtherIUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. XLIX. Nomenclature and Structure-Function Relationships of Transient Receptor Potential Channels

David E. Clapham, David Julius, Craig Montell and Günter Schultz
Pharmacological Reviews December 1, 2005, 57 (4) 427-450; DOI: https://doi.org/10.1124/pr.57.4.6
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