Abstract
Mammalian homologues of the Drosophila melanogaster transient receptor potential (TRP) channels are the second largest cation channel family within the superfamily of hexahelical cation channels. Most mammalian TRP channels function as homooligomers and mediate mono- or divalent cation entry upon activation by a variety of stimuli. Because native TRP channels may be multimeric proteins of possibly complex composition, it is difficult to compare cation conductances in native tissues to those of clearly defined homomeric TRP channel complexes in living cells. Therefore, the possibility of heteromeric TRP channel assembly has been investigated in recent years by several groups. As a major conclusion of these studies, most heteromeric TRP channel complexes appear to consist of subunit combinations only within relatively narrow confines of phylogenetic subfamilies. Although the general capability of heteromer formation between closely related TRP channel subunits is now clearly established, we are only beginning to understand whether these heteromeric complexes are of physiological significance. This review summarizes the current knowledge on the promiscuity and specificity of the assembly of channel complexes composed of TRPC-, TRPV- and TRPM-subunits of mammalian TRP channels.
Similar content being viewed by others
References
Ahluwalia J, Rang H, Nagy I (2002) The putative role of vanilloid receptor-like protein-1 in mediating high threshold noxious heat-sensitivity in rat cultured primary sensory neurons. Eur J Neurosci 16:1483–1489
Amiri H, Schultz G, Schaefer M (2003) FRET-based analysis of TRPC subunit stoichiometry. Cell Calcium 33:463–470
Babnigg G, Heller B, Villereal ML (2000) Cell-to-cell variation in store-operated calcium entry in HEK-293 cells and its impact on the interpretation of data from stable clones expressing exogenous calcium channels. Cell Calcium 27:61–73
Bähner M, Frechter S, Da Silva N, Minke B, Paulsen R, Huber A (2002) Light-regulated subcellular translocation of Drosophila TRPL channels induces long-term adaptation and modifies the light-induced current. Neuron 34:83–93
Balzer M, Lintschinger B, Groschner K (1999) Evidence for a role of Trp proteins in the oxidative stress-induced membrane conductances of porcine aortic endothelial cells. Cardiovasc Res 42:543–549
Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398:436–441
Chang Q, Gyftogianni E, van de Graaf SF, Hoefs S, Weidema FA, Bindels RJ, Hoenderop JG (2004) Molecular determinants in TRPV5 channel assembly. J Biol Chem 279:54304–54311
Chu X, Tong Q, Cheung JY, Wozney J, Conrad K, Mazack V, Zhang W, Stahl R, Barber DL, Miller BA (2004) Interaction of TRPC2 and TRPC6 in erythropoietin modulation of calcium influx. J Biol Chem 279:10514–10522
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 101:2894–2899
Clapham DE, Montell C, Schultz G, Julius D (2003) International union of pharmacology. XLIII. Compendium of voltage-gated ion channels: transient receptor potential channels. Pharmacol Rev 55:591–596
Delmas P (2004) Polycystins: from mechanosensation to gene regulation. Cell 118:145–148
Dietrich A, Mederos y Schnitzler M, Emmel J, Kalwa H, Hofmann T, Gudermann T (2003) N-linked protein glycosylation is a major determinant for basal TRPC3 and TRPC6 channel activity. J Biol Chem 278:47842–47852
Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77
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 279:34456–34463
Fleig A, Penner R (2004) The TRPM ion channel subfamily: molecular, biophysical and functional features. Trends Pharmacol Sci 25:633–639
García-Sanz N, Fernández-Carvajal A, Morenilla-Palao C, Planells-Cases R, Fajardo-Sánchez E, Fernández-Ballester G, Ferrer-Montiel A (2004) Identification of a tetramerization domain in the C terminus of the vanilloid receptor. J Neurosci 24:5307–5314
Gillo B, Chorna I, Cohen H, Cook B, Manistersky I, Chorev M, Arnon A, Pollock JA, Selinger Z, Minke B (1996) Coexpression of Drosophila TRP and TRP-like proteins in Xenopus oocytes reconstitutes capacitative Ca2+ entry. Proc Natl Acad Sci USA 93:14146–14151
Goel M, Sinkins WG, Schilling WP (2002) Selective association of TRPC channel subunits in rat brain synaptosomes. J Biol Chem 277:48303–48310
Greffrath W, Binzen U, Schwarz ST, Saaler-Reinhardt S, Treede RD (2003) Co-expression of heat sensitive vanilloid receptor subtypes in rat dorsal root ganglion neurons. Neuroreport 14:2251–2255
Hellwig N, Albrecht N, Harteneck C, Schultz G, Schaefer M (2005) Homo- and heteromeric assembly of TRPV channel subunits. J Cell Sci 118:917–928
Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ (2003) Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J 22:776–785
Hofmann T, Schaefer M, Schultz G, 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
Hofmann T, Schaefer M, Schultz G, Gudermann T (2002) Subunit composition of mammalian transient receptor potential channels in living cells. Proc Natl Acad Sci USA 99:7461–7466
Huber A (2001) Scaffolding proteins organize multimolecular protein complexes for sensory signal transduction. Eur J Neurosci 14:769–776
Huber A, Sander P, Gobert A, Bahner M, Hermann R, Paulsen R (1996) The transient receptor potential protein (Trp), a putative store-operated Ca2+ channel essential for phosphoinositide-mediated photoreception, forms a signaling complex with NorpA, InaC and InaD. EMBO J 15:7036–7045
Ichikawa H, Sugimoto T (2003) The co-expression of VR1 and VRL-1 in the rat vagal sensory ganglia. Brain Res 980:293–296
Jahnel R, Dreger M, Gillen C, Bender O, Kurreck J, Hucho F (2001) Biochemical characterization of the vanilloid receptor 1 expressed in a dorsal root ganglia derived cell line. Eur J Biochem 268:5489–5496
Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R (2003) X-ray structure of a voltage-dependent K+ channel. Nature 423:33–41
Jordt SE, Julius D (2002) Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108:421–430
Jung J, Lee SY, Hwang SW, Cho H, Shin J, Kang YS, Kim S, Oh U (2002) Agonist recognition sites in the cytosolic tails of vanilloid receptor 1. J Biol Chem 277:44448–44454
Kedei N, Szabo T, Lile JD, Treanor JJ, Olah Z, Iadarola MJ, Blumberg PM (2001) Analysis of the native quaternary structure of vanilloid receptor 1. J Biol Chem 276:28613–28619
Kobertz WR, Miller C (1999) K+ channels lacking the ’tetramerization’ domain: implications for pore structure. Nat Struct Biol 6:1122–1125
Kreusch A, Pfaffinger PJ, Stevens CF, Choe S (1998) Crystal structure of the tetramerization domain of the Shaker potassium channel. Nature 392:945–948
Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA (2003) Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300:1922–1926
Lee-Kwon W, Wade JB, Zhang Z, Pallone TL, Weinman EJ (2005) Expression of TRPC4 channel protein that interacts with NHERF-2 in rat descending vasa recta. Am J Physiol Cell Physiol 288:C942-C949
Leung HT, Geng C, Pak WL (2000) Phenotypes of trpl mutants and interactions between the transient receptor potential (TRP) and TRP-like channels in Drosophila. J Neurosci 20:6797–6803
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 USA 99:6376–6381
Li M, Jan YN, Jan LY (1992) Specification of subunit assembly by the hydrophilic amino-terminal domain of the Shaker potassium channel. Science 257:1225–1230
Li HS, Montell C (2000) TRP and the PDZ protein, INAD, form the core complex required for retention of the signalplex in Drosophila photoreceptor cells. J Cell Biol 150:1411–1422
Liman ER, Corey DP, Dulac C (1999) TRP2: a candidate transduction channel for mammalian pheromone sensory signaling. Proc Natl Acad Sci USA 96:5791–5796
Liman ER, Innan H (2003) Relaxed selective pressure on an essential component of pheromone transduction in primate evolution. Proc Natl Acad Sci USA 100:3328–3332
Lintschinger B, Balzer-Geldsetzer M, Baskaran T, Graier WF, Romanin C, Zhu MX, Groschner K (2000) Coassembly of Trp1 and Trp3 proteins generates diacylglycerol- and Ca2+ -sensitive cation channels. J Biol Chem 275:27799–27805
Liu X, Bandyopadhyay BC, Singh BB, Groschner K, Ambudkar IS (2005) Molecular analysis of a store-operated and OAG sensitive non-selective cation channel: heteromeric assembly of TRPC1-TRPC3. J Biol Chem 17 April 2005 [Epub ahead of print]
Menco BP, Carr VM, Ezeh PI, Liman ER, Yankova MP (2001) Ultrastructural localization of G-proteins and the channel protein TRP2 to microvilli of rat vomeronasal receptor cells. J Comp Neurol 438:468–489
Mery L, Strauss B, Dufour JF, Krause KH, Hoth M (2002) The PDZ-interacting domain of TRPC4 controls its localization and surface expression in HEK293 cells. J Cell Sci 115:3497–3508
Montell C (2005) The TRP superfamily of cation channels. Sci STKE 272:re3
Montell C, Birnbaumer L, Flockerzi V (2002) The TRP channels, a remarkably functional family. Cell 108:595–598
Moqrich A, Hwang SW, Earley TJ, Petrus MJ, Murray AN, Spencer KS, Andahazy M, Story GM, Patapoutian A (2005) Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307:1468–1472
Moran MM, Xu H, Clapham DE (2004) TRP ion channels in the nervous system. Curr Opin Neurobiol 14:362–369
Nadler MJ, Hermosura MC, Inabe K, Perraud AL, Zhu Q, Stokes AJ, Kurosaki T, Kinet JP, Penner R, Scharenberg AM, Fleig A (2001) LTRPC7 is a Mg ATP-regulated divalent cation channel required for cell viability. Nature 411:590–595
Niemeyer BA, Suzuki E, Scott K, Jalink K, Zuker CS (1996) The Drosophila light-activated conductance is composed of the two channels TRP and TRPL. Cell 85:651–659
Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P, Bevan S, Patapoutian A (2002) A heat-sensitive TRP channel expressed in keratinocytes. Science 296:2046–2049
Reuss H, Mojet MH, Chyb S, Hardie RC (1997) In vivo analysis of the Drosophila light-sensitive channels, TRP and TRPL. Neuron 19:1249–1259
Schaefer M, Plant TD, Stresow N, Albrecht N, Schultz G (2002) Functional differences between TRPC4 splice variants. J Biol Chem 277:3752–3759
Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth HW, Konrad M (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31:166–170
Shieh BH, Zhu MY (1996) Regulation of the TRP Ca2+ channel by INAD in Drosophila photoreceptors. Neuron 16:991–998
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 (2002) TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418:186–190
Song X, Zhao Y, Narcisse L, Duffy H, Kress Y, Lee S, Brosnan CF (2005) Canonical transient receptor potential channel 4 (TRPC4) co-localizes with the scaffolding protein ZO-1 in human fetal astrocytes in culture. Glia 49:418–429
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 295:1493–1500
Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 29:645–655
Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE (2003) Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem 278:39014–39019
Tang Y, Tang J, Chen Z, Trost C, Flockerzi V, Li M, Ramesh V, Zhu MX (2000) Association of mammalian Trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF. J Biol Chem 275:37559–37564
Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, Sukhatme VP (1999) Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci USA 96:3934–3939
Tsunoda S, Sierralta J, Sun Y, Bodner R, Suzuki E, Becker A, Socolich M, Zuker CS (1997) A multivalent PDZ-domain protein assembles signalling complexes in a G-protein-coupled cascade. Nature 388:243–249
van Abel M, Hoenderop JG, Bindels RJ (2005) The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease. Naunyn Schmiedebergs Arch Pharmacol (in press)
Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, Hoenderop JG (2004) TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279:19–25
Xu XZ, Chien F, Butler A, Salkoff L, Montell C (2000) TRPγ, a Drosophila TRP-related subunit, forms a regulated cation channel with TRPL. Neuron 26:647–657
Xu XZ, Choudhury A, Li X, Montell C (1998) Coordination of an array of signaling proteins through homo- and heteromeric interactions between PDZ domains and target proteins. J Cell Biol 142:545–555
Xu XZ, Li HS, Guggino WB, Montell C (1997) Coassembly of TRP and TRPL produces a distinct store-operated conductance. Cell 89:1155–1164
Yamaguchi H, Matsushita M, Nairn AC, Kuriyan J (2001) Crystal structure of the atypical protein kinase domain of a TRP channel with phosphotransferase activity. Mol Cell 7:1047–1057
Zhang Z, Tang Y, Zhu MX (2001) Increased inwardly rectifying potassium currents in HEK-293 cells expressing murine transient receptor potential 4. Biochem J 354:717–725
Zitt C, Obukhov AG, Strubing C, Zobel A, Kalkbrenner F, Lückhoff A, Schultz G (1997) Expression of TRPC3 in Chinese hamster ovary cells results in calcium-activated cation currents not related to store depletion. J Cell Biol 138:1333–1341
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schaefer, M. Homo- and heteromeric assembly of TRP channel subunits. Pflugers Arch - Eur J Physiol 451, 35–42 (2005). https://doi.org/10.1007/s00424-005-1467-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-005-1467-6