Abstract
TRPC6 is a Ca2+-permeable non-selective cation channel expressed in brain, smooth muscle containing tissues and kidney, as well as in immune and blood cells. Channel homomers heterologously expressed have a characteristic doubly rectifying current-voltage relationship and are six times more permeable for Ca2+ than for Na+. In smooth muscle tissues, however, Na+ influx and activation of voltage-gated calcium channels by membrane depolarization rather than Ca2+ elevation by TRPC6 channels is the driving force for contraction. TRPC6 channels are directly activated by the second messenger diacylglycerol (DAG) and regulated by specific tyrosine or serine phosphorylation. Extracellular Ca2+ has inhibitory effects, while Ca2+/calmodulin acting from the intracellular side has potentiator effects on channel activity. Given its specific expression, TRPC6 is likely to play a number of physiological roles. Studies with TRPC6 -/- mice suggest a role for the channel in the regulation of vascular and pulmonary smooth muscle contraction. TRPC6 was identified as an essential component of the slit diaphragm architecture of kidney podocytes. Other functions in immune and blood cells, as well as in brain and in smooth muscle-containing tissues such as stomach, colon and myometrium, remain elusive.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bandyopadhyay BC, Swaim WD, Liu X, Redman RS, Patterson RL, Ambudkar IS (2005) Apical localization of a functional TRPC3/TRPC6-Ca2+-signaling complex in polarized epithelial cells. Role in apical Ca2+ influx. J Biol Chem 280:12908–12916
Basora N, Boulay G, Bilodeau L, Rousseau E, Payet MD (2003) 20-hydroxyeicosatetraenoic acid (20-HETE) activates mouse TRPC6 channels expressed in HEK293 cells. J Biol Chem 278:31709–31716
Beech DJ, Muraki K, Flemming R (2004) Non-selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP. J Physiol 559:685–706
Birnbaumer L, Dietrich A, Kawasaki B, Zhu MX (2003) Multiple interactions between TRPCs and IP3Rs: TRPC3-interacting domains of IP3R serve to identify TRPCs as components of CCE channels; yet, IP3R activation does not activate TRPC3 channels. Nova Acta Leopold 89(336):61–67
Bonaventure P, Guo H, Tian B, Liu X, Bittner A, Roland B, Salunga R, Ma XJ, Kamme F, Meurers B, Bakker M, Jurzak M, Leysen JE, Erlander MG (2002) Nuclei and subnuclei gene expression profiling in mammalian brain. Brain Res 943:38–47
Boulay G, Zhu X, Peyton M, Jiang M, Hurst R, Stefani E, Birnbaumer L (1997) Cloning and expression of a novel mammalian homolog of Drosophila transient receptor potential (Trp) involved in calcium entry secondary to activation of receptors coupled by the Gq class of G protein. J Biol Chem 272:29672–29680
Boulay G, Brown DM, Qin N, Jiang M, Dietrich A, Zhu MX, Chen Z, Birnbaumer M, Mikoshiba K, Birnbaumer L (1999) Modulation of Ca(2+) entry by polypeptides of the inositol 1,4,5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca(2+) entry. Proc Natl Acad Sci U S A 96:14955–14960
Buess M, Engler O, Hirsch HH, Moroni C (1999) Search for oncogenic regulators in an autocrine tumor model using differential display PCR: identification of novel candidate genes including the calcium channel mtrp6. Oncogene 18:1487–1494
Cayouette S, Lussier MP, Mathieu EL, Bousquet SM, Boulay G (2004) Exocytotic insertion of TRPC6 channel into the plasma membrane upon Gq protein-coupled receptor activation. J Biol Chem 279:7241–7246
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
Corteling RL, Li S, Giddings J, Westwick J, Poll C, 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
D’Esposito M, Strazzullo M, Cuccurese M, Spalluto C, Rocchi M, D’Urso M, Ciccodicola A (1998) Identification and assignment of the human transient receptor potential channel 6 gene TRPC6 to chromosome 11q21–>q22. Cytogenet Cell Genet 83:46–47
Dietrich A, Gollasch M, Chubanov V, Mederos y Schnitzler M, Dubrovska G, Herz U, Renz H, Gudermann T, Birnbaumer L (2003a) Studies on TRPC6 deficient mice reveal its non-redundant role in the regulation of smooth muscle tone. Naunyn Schmiedebergs Arch Pharmacol 367:238
Dietrich A, Mederos y Schnitzler M, Emmel J, Kalwa H, Hofmann T, Gudermann T (2003b) N-linked protein glycosylation is a major determinant for basal TRPC3 and TRPC6 channel activity. J Biol Chem 278:47842–47852
Dietrich A, Mederos y Schnitzler M, Kalwa H, Storch U, Gudermann T (2005a) Functional characterization and physiological relevance of the TRPC3/6/7 subfamily of cation channels. Naunyn Schmiedebergs Arch Pharmacol 371:257–265
Dietrich A, Kalwa H, Rost BR, Gudermann T (2005b) The diacylglycerol-sensitive TRPC3/6/7 subfamily of cation channels: functional characterization and physiological relevance. Pflügers Arch 451:72–80
Dietrich A, Mederos YSM, Gollasch M, Gross V, Storch U, Dubrovska G, Obst M, Yildirim E, Salanova B, Kalwa H, Essin K, Pinkenburg O, Luft FC, Gudermann T, Birnbaumer L (2005c) Increased vascular smooth muscle contractility in TRPC6-/- mice. Mol Cell Biol 25:6980–6989
Earley S, Waldron BJ, Brayden JE (2004) Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ Res 95:922–929
Elsaesser R, Montani G, Tirindelli R, Paysan J (2005) Phosphatidyl-inositide signaling proteins in a novel class of sensory cells in the mammalian olfactory epithelium. Eur J Neurosci 21:2692–2700
Estacion M, Li S, Sinkins WG, Gosling M, Bahra P, Poll C, Westwick J, Schilling WP (2004) Activation of human TRPC6 channels by receptor stimulation. J Biol Chem 279:22047–22056
Estacion M, Sinkins WG, Jones SW, Applegate MA, Schilling WP (2006) TRPC6 forms non-selective cation channels with limited Ca2+ permeability. J Physiol 572:359–377
Garcia RL, Schilling WP (1997) Differential expression of mammalian TRP homologues across tissues and cell lines. Biochem Biophys Res Commun 239:279–283
Goel M, Sinkins WG, Schilling WP (2002) Selective association of TRPC channel subunits in rat brain synaptosomes. J Biol Chem 277:48303–48310
Goel M, Sinkins W, Keightley A, Kinter M, Schilling WP (2005a) Proteomic analysis of TRPC5-and TRPC6-binding partners reveals interaction with the plasmalemmal Na(+)/K(+)-ATPase. Pflugers Arch 451:87–98
Goel M, Sinkins WG, Zuo CD, Estacion M, Schilling WP (2005b) Identification and localization of TRPC channels in rat kidney. Am J Physiol Renal Physiol 290:F1241–F1252
Gudermann T (2005) A new TRP to kidney disease. Nat Genet 37:663–664
Gudermann T, Mederos y Schnitzler M, Dietrich A (2004) Receptor-operated cation entry-more than esoteric terminology? Sci STKE 243:pe35
Halaszovich C R, Zitt C, Jüngling E, Lückhoff A (2000) Inhibition of TRP3 channels by lanthanides. Block from the cytosolic side of the plasma membrane. J Biol Chem 275:37423–37428
Hassock SR, Zhu MX, Trost C, Flockerzi V, Authi KS (2002) Expression and role of TRPC proteins in human platelets: evidence that TRPC6 forms the store-independent calcium entry channel. Blood 100:2801–2811
Hisatsune C, Kuroda Y, Nakamura K, Inoue T, Nakamura T, Michikawa T, Mizutani A, Mikoshiba K (2004) Regulation of TRPC6 channel activity by tyrosine phosphorylation. J Biol Chem 279:18887–18894
Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G (1999) Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397:259–263
Hofmann T, Schaefer M, Schultz G, Gudermann T (2000) Transient receptor potential channels as molecular substrates of receptor-mediated cation entry. J Mol Med 78:14–25
Hofmann T, Schaefer M, Schultz G, Gudermann T (2002) Subunit composition of mammalian transient receptor potential channels in living cells. Proc Natl Acad Sci U S A 99:7461–7466
Inoue R, Okada T, Onoue H, Hara Y, Shimizu S, Naitoh S, Ito Y, Mori Y (2001) The transient receptor potential protein homologue TRP6 is the essential component of vascular alpha(1)-adrenoceptor-activated Ca(2+)-permeable cation channel. Circ Res 88:325–332
Jung S, Strotmann R, Schultz G, Plant TD (2002) TRPC6 is a candidate channel involved in receptor-stimulated cation currents in A7r5 smooth muscle cells. Am J Physiol Cell Physiol 282:C347–359
Kawasaki BT, Liao Y, Birnbaumer L (2006) Role of Src in C3 transient receptor potential channel function and evidence for a heterogeneous makeup of receptor-and store-operated Ca2+ entry channels. Proc Natl Acad Sci U S A 103:335–340
Kim JY, Saffen D (2005) Activation of M1 muscarinic acetylcholine receptors stimulates the formation of a multiprotein complex centered on TRPC6 channels. J Biol Chem 280:32035–32047
Kriz W (2005) TRPC6—a new podocyte gene involved in focal segmental glomerulosclerosis. Trends Mol Med 11:527–530
Krizaj D (2005) Compartmentalization of calcium entry pathways in mouse rods. Eur J Neurosci 22:3292–3296
Lessard CB, Lussier MP, Cayouette S, Bourque G, Boulay G (2005) The overexpression of presenilin2 and Alzheimer’s-disease-linked presenilin2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells. Cell Signal 17:437–445
Li S, Gosling M, Poll C (2005a) Determining the functional role of TRPC channels in primary cells. Pflugers Arch 451:43–52
Li Y, Jia YC, Cui K, Li N, Zheng ZY, Wang YZ, Yuan XB (2005b) Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor. Nature 434:894–898
Lin MJ, Leung GP, Zhang WM, Yang XR, Yip KP, Tse CM, Sham JS (2004) Chronic hypoxia-induced upregulation of store-operated and receptor-operated Ca2+ channels in pulmonary arterial smooth muscle cells: a novel mechanism of hypoxic pulmonary hypertension. Circ Res 95:496–505
Lu PJ, Hsu AL, Wang DS, Chen CS (1998) Phosphatidylinositol 3,4,5-trisphosphate triggers platelet aggregation by activating Ca2+ influx. Biochemistry 37:9776–9783
Lussier MP, Cayouette S, Lepage PK, Bernier CL, Francoeur N, St-Hilaire M, Pinard M, Boulay G (2005) MxA, amember of the dynamin superfamily, interacts with the ankyrin-like repeat domain of TRPC. J Biol Chem 280:19393–19400
Montell C (2001) Physiology, phylogeny, and functions of the TRP superfamily of cation channels. Sci STKE 90:RE1
Okada T, Inoue R, Yamazaki K, Maeda A, Kurosaki T, Yamakuni T, Tanaka I, Shimizu S, Ikenaka K, Imoto K, Mori Y (1999) Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. Ca(2+)-permeable cation channel that is constitutively activated and enhanced by stimulation of G protein-coupled receptor. J Biol Chem 274:27359–27370
Otsuka Y, Sakagami H, Owada Y, Kondo H (1998) Differential localization of mRNAs for mammalian trps, presumptive capacitative calcium entry channels, in the adult mouse brain. Tohoku J Exp Med 185:139–146
Owsianik G, Talavera K, Voets T, Nilius B (2005) Permeation and selectivity of TRP channels. Annu Rev Physiol 68:685–717
Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR (2005) TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 37:739–744
Shi J, Mori E, Mori Y, Mori M, Li J, Ito Y, Inoue R (2004) Multiple regulation by calcium of murine homologues of transient receptor potential proteins TRPC6 and TRPC7 expressed in HEK293 cells. J Physiol 561:415–432
Soboloff J, Spassova M, Xu W, He LP, Cuesta N, Gill DL (2005) Role of endogenous TRPC6 channels in Ca2+ signal generation in A7r5 smooth muscle cells. J Biol Chem 280:39786–39794
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
Thebault S, Flourakis M, Vanoverberghe K, Vandermoere F, Roudbaraki M, Lehen’kyi V, Slomianny C, Beck B, Mariot P, Bonnal JL, Mauroy B, Shuba Y, Capiod T, Skyrma R, Prevaraskaya N (2006) Different role of transient receptor potential channels in Ca2+ entry and proliferation of prostate cancer epithelial cells. Cancer Res 66:2038–2047
Trebak M, Vazquez G, Bird GS, Putney JW Jr (2003) The TRPC3/6/7 subfamily of cation channels. Cell Calcium 33:451–461
Tseng PH, Lin HP, Hu H, Wang C, Zhu MX, Chen CS (2004) The canonical transient receptor potential 6 channel as a putative phosphatidylinositol 3,4,5-trisphosphate-sensitive calcium entry system. Biochemistry 43:11701–11708
Welsh DG, Morielli AD, Nelson MT, Brayden JE (2002) Transient receptor potential channels regulate myogenic tone of resistance arteries. Circ Res 90:248–250
Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, Daskalakis N, Kwan SY, Ebersviller S, Burchette JL, Pericak-Vance MA, Howell DN, Vance JM, Rosenberg PB (2005) A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308:1801–1804
Yu Y, Sweeney M, Zhang S, Platoshyn O, Landsberg J, Rothman A, Yuan JX (2003) PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am J Physiol Cell Physiol 284:C316–330
Yu Y, Fantozzi I, Remillard CV, Landsberg JW, Kunichika N, Platoshyn O, Tigno DD, Thistlethwaite PA, Rubin LJ, Yuan JX (2004) Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci U S A 101:13861–13866
Zhang L, Saffen D (2001) Muscarinic acetylcholine receptor regulation of TRP6 Ca2+ channel isoforms. Molecular structures and functional characterization. J Biol Chem 276:13331–13339
Zhang Z, Tang J, Tikunova S, Johnson JD, Chen Z, Qin N, Dietrich A, Stefani E, Birnbaumer L, Zhu MX (2001) Activation of Trp3 by inositol 1,4,5-trisphosphate receptors through displacement of inhibitory calmodulin from a common binding domain. Proc Natl Acad Sci U S A 98:3168–3173
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Dietrich, A., Gudermann, T. (2007). TRPC6. In: Flockerzi, V., Nilius, B. (eds) Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology, vol 179. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-34891-7_7
Download citation
DOI: https://doi.org/10.1007/978-3-540-34891-7_7
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-34889-4
Online ISBN: 978-3-540-34891-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)