Skip to main content
SpringerLink
Log in

Homo- and heteromeric assembly of TRP channel subunits

  • Ion Channels, Transporters
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. 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

    Article  PubMed  Google Scholar 

  2. Amiri H, Schultz G, Schaefer M (2003) FRET-based analysis of TRPC subunit stoichiometry. Cell Calcium 33:463–470

    Article  CAS  PubMed  Google Scholar 

  3. 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

    Article  CAS  PubMed  Google Scholar 

  4. 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

    Article  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. 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

    Article  CAS  PubMed  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. 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

    CAS  PubMed  Google Scholar 

  10. 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

    Article  PubMed  Google Scholar 

  11. Delmas P (2004) Polycystins: from mechanosensation to gene regulation. Cell 118:145–148

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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

    Article  CAS  PubMed  Google Scholar 

  15. Fleig A, Penner R (2004) The TRPM ion channel subfamily: molecular, biophysical and functional features. Trends Pharmacol Sci 25:633–639

    CAS  PubMed  Google Scholar 

  16. 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

    Article  CAS  PubMed  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. Goel M, Sinkins WG, Schilling WP (2002) Selective association of TRPC channel subunits in rat brain synaptosomes. J Biol Chem 277:48303–48310

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  CAS  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. Huber A (2001) Scaffolding proteins organize multimolecular protein complexes for sensory signal transduction. Eur J Neurosci 14:769–776

    Article  CAS  PubMed  Google Scholar 

  25. 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

    CAS  PubMed  Google Scholar 

  26. Ichikawa H, Sugimoto T (2003) The co-expression of VR1 and VRL-1 in the rat vagal sensory ganglia. Brain Res 980:293–296

    Google Scholar 

  27. 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

    CAS  PubMed  Google Scholar 

  28. 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

    Article  CAS  PubMed  Google Scholar 

  29. Jordt SE, Julius D (2002) Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108:421–430

    Article  CAS  PubMed  Google Scholar 

  30. 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

    Article  CAS  PubMed  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. Kobertz WR, Miller C (1999) K+ channels lacking the ’tetramerization’ domain: implications for pore structure. Nat Struct Biol 6:1122–1125

    Article  CAS  PubMed  Google Scholar 

  33. Kreusch A, Pfaffinger PJ, Stevens CF, Choe S (1998) Crystal structure of the tetramerization domain of the Shaker potassium channel. Nature 392:945–948

    Article  CAS  PubMed  Google Scholar 

  34. 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

    Article  CAS  PubMed  Google Scholar 

  35. 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

    Article  CAS  PubMed  Google Scholar 

  36. 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

    Google Scholar 

  37. 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

    Article  CAS  PubMed  Google Scholar 

  38. 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

    CAS  PubMed  Google Scholar 

  39. 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

    Article  CAS  PubMed  Google Scholar 

  40. 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

    Article  CAS  PubMed  Google Scholar 

  41. 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

    Article  CAS  PubMed  Google Scholar 

  42. 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

    CAS  PubMed  Google Scholar 

  43. 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]

  44. 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

    Article  CAS  PubMed  Google Scholar 

  45. 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

    CAS  PubMed  Google Scholar 

  46. Montell C (2005) The TRP superfamily of cation channels. Sci STKE 272:re3

    Article  Google Scholar 

  47. Montell C, Birnbaumer L, Flockerzi V (2002) The TRP channels, a remarkably functional family. Cell 108:595–598

    CAS  PubMed  Google Scholar 

  48. 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

    Article  CAS  PubMed  Google Scholar 

  49. Moran MM, Xu H, Clapham DE (2004) TRP ion channels in the nervous system. Curr Opin Neurobiol 14:362–369

    Article  CAS  PubMed  Google Scholar 

  50. 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

    CAS  PubMed  Google Scholar 

  51. 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

    Article  CAS  PubMed  Google Scholar 

  52. 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

    Article  CAS  PubMed  Google Scholar 

  53. 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

    Article  CAS  PubMed  Google Scholar 

  54. Schaefer M, Plant TD, Stresow N, Albrecht N, Schultz G (2002) Functional differences between TRPC4 splice variants. J Biol Chem 277:3752–3759

    Article  CAS  PubMed  Google Scholar 

  55. 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

    Article  CAS  PubMed  Google Scholar 

  56. Shieh BH, Zhu MY (1996) Regulation of the TRP Ca2+ channel by INAD in Drosophila photoreceptors. Neuron 16:991–998

    Article  CAS  PubMed  Google Scholar 

  57. 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

    Article  CAS  PubMed  Google Scholar 

  58. 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

    Article  PubMed  Google Scholar 

  59. 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  61. 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

    Article  PubMed  Google Scholar 

  62. 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

    Article  CAS  PubMed  Google Scholar 

  63. 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

    Article  CAS  PubMed  Google Scholar 

  64. 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

    Article  CAS  PubMed  Google Scholar 

  65. 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)

    Google Scholar 

  66. 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

    CAS  PubMed  Google Scholar 

  67. 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

    Article  CAS  PubMed  Google Scholar 

  68. 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  70. 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

    Article  CAS  PubMed  Google Scholar 

  71. 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

    Article  CAS  PubMed  Google Scholar 

  72. 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

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Pharmakologie, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Thielallee 67–73, 14195, Berlin, Germany

    Michael Schaefer

Authors
  1. Michael Schaefer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Schaefer.

Rights and permissions

Reprints 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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-005-1467-6

Keywords

Search

Navigation