Skip to main content

TRPC6: Physiological Function and Pathophysiological Relevance

  • Chapter
  • First Online:
Mammalian Transient Receptor Potential (TRP) Cation Channels

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 222))

Abstract

TRPC6 is a non-selective cation channel 6 times more permeable to Ca2+ than to Na+. Channel homotetramers heterologously expressed have a characteristic doubly rectifying current-voltage relationship and are directly activated by the second messenger diacylglycerol (DAG). TRPC6 proteins are also regulated by specific tyrosine or serine phosphorylation and phosphoinositides. Given its specific expression pattern, TRPC6 is likely to play a number of physiological roles which are confirmed by the analysis of a Trpc6 −/− mouse model. In smooth muscle Na+ influx through TRPC6 channels and activation of voltage-gated Ca2+ channels by membrane depolarisation is the driving force for contraction. Permeability of pulmonary endothelial cells depends on TRPC6 and induces ischaemia–reperfusion oedema formation in the lungs. TRPC6 was also identified as an essential component of the slit diaphragm architecture of kidney podocytes and plays an important role in the protection of neurons after cerebral ischaemia. Other functions especially in immune and blood cells remain elusive. Recently identified TRPC6 blockers may be helpful for therapeutic approaches in diseases with highly activated TRPC6 channel activity.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

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(13):12908–12916. doi:10.1074/jbc.M410013200

    PubMed  CAS  Google Scholar 

  • 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(34):31709–31716. doi:10.1074/jbc.M304437200

    PubMed  CAS  Google Scholar 

  • Beech DJ, Muraki K, Flemming R (2004) Non-selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP. J Physiol 559(Pt 3):685–706. doi:10.1113/jphysiol.2004.068734 [pii]

    PubMed Central  PubMed  CAS  Google Scholar 

  • Beis D, Schwarting RK, Dietrich A (2011) Evidence for a supportive role of classical transient receptor potential 6 (TRPC6) in the exploration behavior of mice. Physiol Behav 102(2):245–250. doi:10.1016/j.physbeh.2010.11.002

    PubMed  CAS  Google Scholar 

  • Berna-Erro A, Galan C, Dionisio N, Gomez LJ, Salido GM, Rosado JA (2012) Capacitative and non-capacitative signaling complexes in human platelets. Biochim Biophys Acta 1823(8):1242–1251. doi:10.1016/j.bbamcr.2012.05.023

    PubMed  CAS  Google Scholar 

  • Bernaldo de Quiros S, Merlo A, Secades P, Zambrano I, de Santa Maria IS, Ugidos N, Jantus-Lewintre E, Sirera R, Suarez C, Chiara MD (2013) Identification of TRPC6 as a possible candidate target gene within an amplicon at 11q21-q22.2 for migratory capacity in head and neck squamous cell carcinomas. BMC Cancer 13:116. doi:10.1186/1471-2407-13-116

    PubMed Central  PubMed  CAS  Google Scholar 

  • Bily J, Grycova L, Holendova B, Jirku M, Janouskova H, Bousova K, Teisinger J (2013) Characterization of the S100A1 protein binding site on TRPC6 C-terminus. PLoS One 8(5):e62677. doi:10.1371/journal.pone.0062677

    PubMed Central  PubMed  CAS  Google Scholar 

  • 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(1):38–47

    PubMed  CAS  Google Scholar 

  • Bootman MD, Collins TJ, Mackenzie L, Roderick HL, Berridge MJ, Peppiatt CM (2002) 2-aminoethoxydiphenyl borate (2-APB) is a reliable blocker of store-operated Ca2+ entry but an inconsistent inhibitor of InsP3-induced Ca2+ release. FASEB J 16(10):1145–1150. doi:10.1096/fj.02-0037rev

    PubMed  CAS  Google Scholar 

  • 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(47):29672–29680

    PubMed  CAS  Google Scholar 

  • 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 USA 96(26):14955–14960

    PubMed Central  PubMed  CAS  Google Scholar 

  • Bousquet SM, Monet M, Boulay G (2010) Protein kinase C-dependent phosphorylation of transient receptor potential canonical 6 (TRPC6) on serine 448 causes channel inhibition. J Biol Chem 285(52):40534–40543. doi:10.1074/jbc.M110.160051

    PubMed Central  PubMed  CAS  Google Scholar 

  • Bousquet SM, Monet M, Boulay G (2011) The serine 814 of TRPC6 is phosphorylated under unstimulated conditions. PLoS One 6(3):e18121. doi:10.1371/journal.pone.0018121

    PubMed Central  PubMed  CAS  Google Scholar 

  • Braun A, Varga-Szabo D, Kleinschnitz C, Pleines I, Bender M, Austinat M, Bosl M, Stoll G, Nieswandt B (2009) Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation. Blood 113(9):2056–2063. doi:10.1182/blood-2008-07-171611

    PubMed  CAS  Google Scholar 

  • Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820. doi:10.1038/414813a

    PubMed  CAS  Google Scholar 

  • Cahalan MD (2009) STIMulating store-operated Ca(2+) entry. Nat Cell Biol 11(6):669–677. doi:10.1038/ncb0609-669 [pii]

    PubMed Central  PubMed  CAS  Google Scholar 

  • Cai R, Ding X, Zhou K, Shi Y, Ge R, Ren G, Jin Y, Wang Y (2009) Blockade of TRPC6 channels induced G2/M phase arrest and suppressed growth in human gastric cancer cells. Int J Cancer 125(10):2281–2287. doi:10.1002/ijc.24551

    PubMed  CAS  Google Scholar 

  • Carrillo C, Hichami A, Andreoletti P, Cherkaoui-Malki M, del Mar Cavia M, Abdoul-Azize S, Alonso-Torre SR, Khan NA (2012) Diacylglycerol-containing oleic acid induces increases in [Ca(2+)](i) via TRPC3/6 channels in human T-cells. Biochim Biophys Acta 1821(4):618–626. doi:10.1016/j.bbalip.2012.01.008

    PubMed  CAS  Google Scholar 

  • 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(8):7241–7246. doi:10.1074/jbc.M312042200

    PubMed  CAS  Google Scholar 

  • Chaudhuri P, Colles SM, Bhat M, Van Wagoner DR, Birnbaumer L, Graham LM (2008) Elucidation of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement. Mol Biol Cell 19(8):3203–3211. doi:10.1091/mbc.E07-08-0765

    PubMed Central  PubMed  CAS  Google Scholar 

  • Chen W, Oberwinkler H, Werner F, Gassner B, Nakagawa H, Feil R, Hofmann F, Schlossmann J, Dietrich A, Gudermann T, Nishida M, Del Galdo S, Wieland T, Kuhn M (2013) Atrial natriuretic peptide-mediated inhibition of microcirculatory endothelial Ca2+ and permeability response to histamine involves cGMP-dependent protein kinase I and TRPC6 channels. Arterioscler Thromb Vasc Biol. doi:10.1161/ATVBAHA.113.001974

    Google Scholar 

  • Cheng HW, James AF, Foster RR, Hancox JC, Bates DO (2006) VEGF activates receptor-operated cation channels in human microvascular endothelial cells. Arterioscler Thromb Vasc Biol 26(8):1768–1776. doi:10.1161/01.ATV.0000231518.86795.0f

    PubMed  CAS  Google Scholar 

  • Chigurupati S, Venkataraman R, Barrera D, Naganathan A, Madan M, Paul L, Pattisapu JV, Kyriazis GA, Sugaya K, Bushnev S, Lathia JD, Rich JN, Chan SL (2010) Receptor channel TRPC6 is a key mediator of Notch-driven glioblastoma growth and invasiveness. Cancer Res 70(1):418–427. doi:10.1158/0008-5472.CAN-09-2654

    PubMed  CAS  Google Scholar 

  • Chiluiza D, Krishna S, Schumacher VA, Schlondorff J (2013) Gain-of-function mutations in transient receptor potential C6 (TRPC6) activate extracellular-signal-regulated kinases Erk1/2. J Biol Chem. doi:10.1074/jbc.M113.463059

    PubMed  Google Scholar 

  • Clementi E, Meldolesi J (1996) Pharmacological and functional properties of voltage-independent Ca2+ channels. Cell Calcium 19(4):269–279

    PubMed  CAS  Google Scholar 

  • 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(1–2):46–47. doi: 10.1159.00001.1.5

    PubMed  Google Scholar 

  • Damann N, Owsianik G, Li S, Poll C, Nilius B (2009) The calcium-conducting ion channel transient receptor potential canonical 6 is involved in macrophage inflammatory protein-2-induced migration of mouse neutrophils. Acta Physiol (Oxf) 195(1):3–11. doi:10.1111/j.1748-1716.2008.01918.x

    CAS  Google Scholar 

  • Davis J, Burr AR, Davis GF, Birnbaumer L, Molkentin JD (2012) A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev Cell 23(4):705–715. doi:10.1016/j.devcel.2012.08.017

    PubMed Central  PubMed  CAS  Google Scholar 

  • DeHaven WI, Jones BF, Petranka JG, Smyth JT, Tomita T, Bird GS, Putney JW Jr (2009) TRPC channels function independently of STIM1 and Orai1. J Physiol 587(Pt 10):2275–2298. doi:10.1113/jphysiol.2009.170431

    PubMed Central  PubMed  CAS  Google Scholar 

  • Dhennin-Duthille I, Gautier M, Faouzi M, Guilbert A, Brevet M, Vaudry D, Ahidouch A, Sevestre H, Ouadid-Ahidouch H (2011) High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters. Cell Physiol Biochem 28(5):813–822. doi: 10.1159.00033.7.5

    PubMed  CAS  Google Scholar 

  • Dietrich A, Gudermann T (2011) TRP channels in the cardiopulmonary vasculature. Adv Exp Med Biol 704:781–810. doi:10.1007/978-94-007-0265-3_41

    PubMed  CAS  Google Scholar 

  • 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(48):47842–47852

    PubMed  CAS  Google Scholar 

  • 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 (2005) Increased vascular smooth muscle contractility in TRPC6-/- mice. Mol Cell Biol 25(16):6980–6989

    PubMed Central  PubMed  CAS  Google Scholar 

  • Dietrich A, Kalwa H, Fuchs B, Grimminger F, Weissmann N, Gudermann T (2007) In vivo TRPC functions in the cardiopulmonary vasculature. Cell Calcium 42(2):233–244. doi:10.1016/j.ceca.2007.02.009, S0143-4160(07)00045-0 [pii]

    PubMed  CAS  Google Scholar 

  • Dietrich A, Chubanov V, Gudermann T (2010) Renal TRPathies. J Am Soc Nephrol 21(5):736–744. doi:10.1681/ASN.2009090948

    PubMed  CAS  Google Scholar 

  • Du W, Huang J, Yao H, Zhou K, Duan B, Wang Y (2010) Inhibition of TRPC6 degradation suppresses ischemic brain damage in rats. J Clin Invest 120(10):3480–3492. doi:10.1172/JCI43165

    PubMed Central  PubMed  CAS  Google Scholar 

  • Eckel J, Lavin PJ, Finch EA, Mukerji N, Burch J, Gbadegesin R, Wu G, Bowling B, Byrd A, Hall G, Sparks M, Zhang ZS, Homstad A, Barisoni L, Birbaumer L, Rosenberg P, Winn MP (2011) TRPC6 enhances angiotensin II-induced albuminuria. J Am Soc Nephrol 22(3):526–535. doi:10.1681/ASN.2010050522

    PubMed Central  PubMed  CAS  Google Scholar 

  • El Boustany C, Bidaux G, Enfissi A, Delcourt P, Prevarskaya N, Capiod T (2008) Capacitative calcium entry and transient receptor potential canonical 6 expression control human hepatoma cell proliferation. Hepatology 47(6):2068–2077. doi:10.1002/hep.22263

    PubMed  Google Scholar 

  • Elsaesser R, Montani G, Tirindelli R, Paysan J (2005) Phosphatidyl-inositide signalling proteins in a novel class of sensory cells in the mammalian olfactory epithelium. Eur J Neurosci 21(10):2692–2700. doi:10.1111/j.1460-9568.2005.04108.x

    PubMed  Google Scholar 

  • 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(21):22047–22056. doi:10.1074/jbc.M402320200

    PubMed  CAS  Google Scholar 

  • Estacion M, Sinkins WG, Jones SW, Applegate MA, Schilling WP (2006) Human TRPC6 expressed in HEK 293 cells forms non-selective cation channels with limited Ca2+ permeability. J Physiol 572(Pt 2):359–377

    PubMed Central  PubMed  CAS  Google Scholar 

  • Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14(9):931–938. doi:10.1038/nm.1857

    PubMed  CAS  Google Scholar 

  • Finney-Hayward TK, Popa MO, Bahra P, Li S, Poll CT, Gosling M, Nicholson AG, Russell RE, Kon OM, Jarai G, Westwick J, Barnes PJ, Donnelly LE (2010) Expression of transient receptor potential C6 channels in human lung macrophages. Am J Respir Cell Mol Biol 43(3):296–304. doi:10.1165/rcmb.2008-0373OC

    PubMed  CAS  Google Scholar 

  • Fleming I, Rueben A, Popp R, Fisslthaler B, Schrodt S, Sander A, Haendeler J, Falck JR, Morisseau C, Hammock BD, Busse R (2007) Epoxyeicosatrienoic acids regulate Trp channel dependent Ca2+ signaling and hyperpolarization in endothelial cells. Arterioscler Thromb Vasc Biol 27(12):2612–2618. doi:10.1161/ATVBAHA.107.152074

    PubMed  CAS  Google Scholar 

  • Foller M, Kasinathan RS, Koka S, Lang C, Shumilina E, Birnbaumer L, Lang F, Huber SM (2008) TRPC6 contributes to the Ca(2+) leak of human erythrocytes. Cell Physiol Biochem 21(1–3):183–192. doi:10.1159.00011.7.0

    PubMed  Google Scholar 

  • Fuchs B, Rupp M, Ghofrani HA, Schermuly RT, Seeger W, Grimminger F, Gudermann T, Dietrich A, Weissmann N (2011) Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6. Respir Res 12:20. doi:10.1186/1465-9921-12-20

    PubMed Central  PubMed  CAS  Google Scholar 

  • Ge R, Tai Y, Sun Y, Zhou K, Yang S, Cheng T, Zou Q, Shen F, Wang Y (2009) Critical role of TRPC6 channels in VEGF-mediated angiogenesis. Cancer Lett 283(1):43–51. doi:10.1016/j.canlet.2009.03.023

    PubMed  CAS  Google Scholar 

  • Gibon J, Tu P, Bohic S, Richaud P, Arnaud J, Zhu M, Boulay G, Bouron A (2011) The over-expression of TRPC6 channels in HEK-293 cells favours the intracellular accumulation of zinc. Biochim Biophys Acta 1808(12):2807–2818. doi:10.1016/j.bbamem.2011.08.013

    PubMed  CAS  Google Scholar 

  • Goel M, Sinkins WG, Schilling WP (2002) Selective association of TRPC channel subunits in rat brain synaptosomes. J Biol Chem 277(50):48303–48310

    PubMed  CAS  Google Scholar 

  • Goel M, Sinkins W, Keightley A, Kinter M, Schilling WP (2005) Proteomic analysis of TRPC5- and TRPC6-binding partners reveals interaction with the plasmalemmal Na(+)/K(+)-ATPase. Pflugers Arch 451(1):87–98

    PubMed  CAS  Google Scholar 

  • Goel M, Sinkins WG, Zuo CD, Estacion M, Schilling WP (2006) Identification and localization of TRPC channels in the rat kidney. Am J Physiol Renal Physiol 290(5):F1241–F1252. doi:10.1152/ajprenal.00376.2005

    PubMed  CAS  Google Scholar 

  • Goel M, Zuo CD, Sinkins WG, Schilling WP (2007) TRPC3 channels colocalize with Na+/Ca2+ exchanger and Na + pump in axial component of transverse-axial tubular system of rat ventricle. Am J Physiol Heart Circ Physiol 292(2):H874–H883. doi:10.1152/ajpheart.00785.2006

    PubMed  CAS  Google Scholar 

  • Goonasekera SA, Molkentin JD (2012) Unraveling the secrets of a double life: contractile versus signaling Ca2+ in a cardiac myocyte. J Mol Cell Cardiol 52(2):317–322. doi:10.1016/j.yjmcc.2011.05.001

    PubMed  CAS  Google Scholar 

  • Gottlieb P, Folgering J, Maroto R, Raso A, Wood TG, Kurosky A, Bowman C, Bichet D, Patel A, Sachs F, Martinac B, Hamill OP, Honore E (2008) Revisiting TRPC1 and TRPC6 mechanosensitivity. Pflugers Arch 455(6):1097–1103. doi:10.1007/s00424-007-0359-3

    PubMed  CAS  Google Scholar 

  • Graham S, Ding M, Sours-Brothers S, Yorio T, Ma JX, Ma R (2007) Downregulation of TRPC6 protein expression by high glucose, a possible mechanism for the impaired Ca2+ signaling in glomerular mesangial cells in diabetes. Am J Physiol Renal Physiol 293(4):F1381–F1390. doi:10.1152/ajprenal.00185.2007

    PubMed  CAS  Google Scholar 

  • Graham S, Gorin Y, Abboud HE, Ding M, Lee DY, Shi H, Ding Y, Ma R (2011) Abundance of TRPC6 protein in glomerular mesangial cells is decreased by ROS and PKC in diabetes. Am J Physiol Cell Physiol 301(2):C304–C315. doi:10.1152/ajpcell.00014.2011

    PubMed Central  PubMed  CAS  Google Scholar 

  • Gudermann T (2005) A new TRP to kidney disease. Nat Genet 37(7):663–664. doi:10.1038/ng0705-663

    PubMed  CAS  Google Scholar 

  • Gudermann T, Mederos y Schnitzler M, Dietrich A (2004) Receptor-operated cation entry—more than esoteric terminology? Sci STKE 2004(243):pe35

    Google Scholar 

  • Guilbert A, Dhennin-Duthille I, Hiani YE, Haren N, Khorsi H, Sevestre H, Ahidouch A, Ouadid-Ahidouch H (2008) Expression of TRPC6 channels in human epithelial breast cancer cells. BMC Cancer 8:125. doi:10.1186/1471-2407-8-125

    PubMed Central  PubMed  Google Scholar 

  • Halaszovich CR, Zitt C, Jungling E, Luckhoff A (2000) Inhibition of TRP3 channels by lanthanides. Block from the cytosolic side of the plasma membrane. J Biol Chem 275(48):37423–37428. doi:10.1074/jbc.M007010200

    PubMed  CAS  Google Scholar 

  • Harper MT, Londono JE, Quick K, Londono JC, Flockerzi V, Philipp SE, Birnbaumer L, Freichel M, Poole AW (2013) Transient receptor potential channels function as a coincidence signal detector mediating phosphatidylserine exposure. Sci Signal 6(281):ra50. doi:10.1126/scisignal.2003701

    PubMed  Google Scholar 

  • Harteneck C, Klose C, Krautwurst D (2011) Synthetic modulators of TRP channel activity. Adv Exp Med Biol 704:87–106. doi:10.1007/978-94-007-0265-3_4

    PubMed  CAS  Google Scholar 

  • Hartmann J, Dragicevic E, Adelsberger H, Henning HA, Sumser M, Abramowitz J, Blum R, Dietrich A, Freichel M, Flockerzi V, Birnbaumer L, Konnerth A (2008) TRPC3 channels are required for synaptic transmission and motor coordination. Neuron 59(3):392–398. doi:10.1016/j.neuron.2008.06.009

    PubMed Central  PubMed  CAS  Google Scholar 

  • 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(8):2801–2811. doi:10.1182/blood-2002-03-0723

    PubMed  CAS  Google Scholar 

  • Hill K, McNulty S, Randall AD (2004) Inhibition of TRPM2 channels by the antifungal agents clotrimazole and econazole. Naunyn Schmiedebergs Arch Pharmacol 370(4):227–237. doi:10.1007/s00210-004-0981-y

    PubMed  CAS  Google Scholar 

  • 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(18):18887–18894. doi:10.1074/jbc.M311274200

    PubMed  CAS  Google Scholar 

  • 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(6716):259–263

    PubMed  CAS  Google Scholar 

  • 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(1):14–25

    PubMed  CAS  Google Scholar 

  • 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(11):7461–7466

    PubMed Central  PubMed  CAS  Google Scholar 

  • Hsu YJ, Hoenderop JG, Bindels RJ (2007) TRP channels in kidney disease. Biochim Biophys Acta 1772(8):928–936. doi:10.1016/j.bbadis.2007.02.001

    PubMed  CAS  Google Scholar 

  • Huber TB, Schermer B, Benzing T (2007) Podocin organizes ion channel-lipid supercomplexes: implications for mechanosensation at the slit diaphragm. Nephron Exp Nephrol 106(2):e27–e31. doi:10.1159.00010.7.9

    PubMed  CAS  Google Scholar 

  • 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(3):325–332

    PubMed  CAS  Google Scholar 

  • Jardin I, Gomez LJ, Salido GM, Rosado JA (2009) Dynamic interaction of hTRPC6 with the Orai1-STIM1 complex or hTRPC3 mediates its role in capacitative or non-capacitative Ca(2+) entry pathways. Biochem J 420(2):267–276. doi:10.1042/BJ20082179

    PubMed  CAS  Google Scholar 

  • Jia Y, Zhou J, Tai Y, Wang Y (2007) TRPC channels promote cerebellar granule neuron survival. Nat Neurosci 10(5):559–567. doi:10.1038/nn1870

    PubMed  CAS  Google Scholar 

  • 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(2):C347–C359

    PubMed  CAS  Google Scholar 

  • Jung S, Muhle A, Schaefer M, Strotmann R, Schultz G, Plant TD (2003) Lanthanides potentiate TRPC5 currents by an action at extracellular sites close to the pore mouth. J Biol Chem 278(6):3562–3571. doi:10.1074/jbc.M211484200

    PubMed  CAS  Google Scholar 

  • Kanda S, Harita Y, Shibagaki Y, Sekine T, Igarashi T, Inoue T, Hattori S (2011) Tyrosine phosphorylation-dependent activation of TRPC6 regulated by PLC-gamma1 and nephrin: effect of mutations associated with focal segmental glomerulosclerosis. Mol Biol Cell 22(11):1824–1835. doi:10.1091/mbc.E10-12-0929

    PubMed Central  PubMed  CAS  Google Scholar 

  • 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 USA 103(2):335–340

    PubMed Central  PubMed  CAS  Google Scholar 

  • Keseru B, Barbosa-Sicard E, Popp R, Fisslthaler B, Dietrich A, Gudermann T, Hammock BD, Falck JR, Weissmann N, Busse R, Fleming I (2008) Epoxyeicosatrienoic acids and the soluble epoxide hydrolase are determinants of pulmonary artery pressure and the acute hypoxic pulmonary vasoconstrictor response. FASEB J 22(12):4306–4315. doi:10.1096/fj.08-112821, fj.08-112821 [pii]

    PubMed Central  PubMed  Google Scholar 

  • 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(36):32035–32047. doi:10.1074/jbc.M500429200

    PubMed  CAS  Google Scholar 

  • Kini V, Chavez A, Mehta D (2010) A new role for PTEN in regulating transient receptor potential canonical channel 6-mediated Ca2+ entry, endothelial permeability, and angiogenesis. J Biol Chem 285(43):33082–33091. doi:10.1074/jbc.M110.142034

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kinoshita H, Kuwahara K, Nishida M, Jian Z, Rong X, Kiyonaka S, Kuwabara Y, Kurose H, Inoue R, Mori Y, Li Y, Nakagawa Y, Usami S, Fujiwara M, Yamada Y, Minami T, Ueshima K, Nakao K (2010) Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart. Circ Res 106(12):1849–1860. doi:10.1161/CIRCRESAHA.109.208314

    PubMed  CAS  Google Scholar 

  • Kiso H, Ohba T, Iino K, Sato K, Terata Y, Murakami M, Ono K, Watanabe H, Ito H (2013) Sildenafil prevents the up-regulation of transient receptor potential canonical channels in the development of cardiomyocyte hypertrophy. Biochem Biophys Res Commun. doi:10.1016/j.bbrc.2013.06.002

    Google Scholar 

  • Klaiber M, Kruse M, Volker K, Schroter J, Feil R, Freichel M, Gerling A, Feil S, Dietrich A, Londono JE, Baba HA, Abramowitz J, Birnbaumer L, Penninger JM, Pongs O, Kuhn M (2010) Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2. Basic Res Cardiol 105(5):583–595. doi:10.1007/s00395-010-0098-z

    PubMed Central  PubMed  CAS  Google Scholar 

  • Klaiber M, Dankworth B, Kruse M, Hartmann M, Nikolaev VO, Yang RB, Volker K, Gassner B, Oberwinkler H, Feil R, Freichel M, Groschner K, Skryabin BV, Frantz S, Birnbaumer L, Pongs O, Kuhn M (2011) A cardiac pathway of cyclic GMP-independent signaling of guanylyl cyclase A, the receptor for atrial natriuretic peptide. Proc Natl Acad Sci USA 108(45):18500–18505. doi:10.1073/pnas.1103300108

    PubMed Central  PubMed  CAS  Google Scholar 

  • Koitabashi N, Aiba T, Hesketh GG, Rowell J, Zhang M, Takimoto E, Tomaselli GF, Kass DA (2010) Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation Novel mechanism of cardiac stress modulation by PDE5 inhibition. J Mol Cell Cardiol 48(4):713–724. doi:10.1016/j.yjmcc.2009.11.015

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kriz W (2005) TRPC6—a new podocyte gene involved in focal segmental glomerulosclerosis. Trends Mol Med 11(12):527–530. doi:10.1016/j.molmed.2005.10.001

    PubMed  CAS  Google Scholar 

  • Krizaj D (2005) Compartmentalization of calcium entry pathways in mouse rods. Eur J Neurosci 22(12):3292–3296. doi:10.1111/j.1460-9568.2005.04469.x

    PubMed Central  PubMed  Google Scholar 

  • Kuwahara K, Wang Y, McAnally J, Richardson JA, Bassel-Duby R, Hill JA, Olson EN (2006) TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest 116(12):3114–3126. doi:10.1172/JCI27702

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kwon Y, Hofmann T, Montell C (2007) Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6. Mol Cell 25(4):491–503. doi:10.1016/j.molcel.2007.01.021

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lang E, Qadri SM, Lang F (2012) Killing me softly—suicidal erythrocyte death. Int J Biochem Cell Biol 44(8):1236–1243. doi:10.1016/j.biocel.2012.04.019

    PubMed  CAS  Google Scholar 

  • Leuner K, Kazanski V, Muller M, Essin K, Henke B, Gollasch M, Harteneck C, Muller WE (2007) Hyperforin–a key constituent of St. John’s wort specifically activates TRPC6 channels. FASEB J 21(14):4101–4111. doi:10.1096/fj.07-8110com

    PubMed  CAS  Google Scholar 

  • Leuner K, Heiser JH, Derksen S, Mladenov MI, Fehske CJ, Schubert R, Gollasch M, Schneider G, Harteneck C, Chatterjee SS, Muller WE (2010) Simple 2,4-diacylphloroglucinols as classic transient receptor potential-6 activators–identification of a novel pharmacophore. Mol Pharmacol 77(3):368–377. doi:10.1124/mol.109.057513

    PubMed  CAS  Google Scholar 

  • Li Y, Jia YC, Cui K, Li N, Zheng ZY, Wang YZ, Yuan XB (2005) Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor. Nature 434(7035):894–898. doi:10.1038/nature03477

    PubMed  CAS  Google Scholar 

  • Liao Y, Erxleben C, Abramowitz J, Flockerzi V, Zhu MX, Armstrong DL, Birnbaumer L (2008) Functional interactions among Orai1, TRPCs, and STIM1 suggest a STIM-regulated heteromeric Orai/TRPC model for SOCE/Icrac channels. Proc Natl Acad Sci USA 105(8):2895–2900. doi:10.1073/pnas.0712288105

    PubMed Central  PubMed  CAS  Google Scholar 

  • Liao Y, Plummer NW, George MD, Abramowitz J, Zhu MX, Birnbaumer L (2009) A role for Orai in TRPC-mediated Ca2+ entry suggests that a TRPC:Orai complex may mediate store and receptor operated Ca2+ entry. Proc Natl Acad Sci USA 106(9):3202–3206. doi:10.1073/pnas.0813346106, 0813346106 [pii]

    PubMed Central  PubMed  CAS  Google Scholar 

  • 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(5):496–505. doi:10.1161/01.RES.0000138952.16382.ad

    PubMed  CAS  Google Scholar 

  • Lin Y, Chen F, Zhang J, Wang T, Wei X, Wu J, Feng Y, Dai Z, Wu Q (2013a) Neuroprotective effect of resveratrol on ischemia/reperfusion injury in rats through TRPC6/CREB pathways. J Mol Neurosci 50(3):504–513. doi:10.1007/s12031-013-9977-8

    PubMed  CAS  Google Scholar 

  • Lin Y, Zhang JC, Fu J, Chen F, Wang J, Wu ZL, Yuan SY (2013b) Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation. J Cereb Blood Flow Metab 33(2):253–262. doi:10.1038/jcbfm.2012.164

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lindemann O, Umlauf D, Frank S, Schimmelpfennig S, Bertrand J, Pap T, Hanley PJ, Fabian A, Dietrich A, Schwab A (2013) TRPC6 regulates CXCR2-mediated chemotaxis of murine neutrophils. J Immunol 190(11):5496–5505. doi:10.4049/jimmunol.1201502

    PubMed  CAS  Google Scholar 

  • Lu PJ, Hsu AL, Wang DS, Chen CS (1998) Phosphatidylinositol 3,4,5-trisphosphate triggers platelet aggregation by activating Ca2+ influx. Biochemistry 37(27):9776–9783. doi:10.1021/bi980163o

    PubMed  CAS  Google Scholar 

  • Lussier MP, Cayouette S, Lepage PK, Bernier CL, Francoeur N, St-Hilaire M, Pinard M, Boulay G (2005) MxA, a member of the dynamin superfamily, interacts with the ankyrin-like repeat domain of TRPC. J Biol Chem 280(19):19393–19400

    PubMed  CAS  Google Scholar 

  • Mederos y Schnitzler M, Storch U, Meibers S, Nurwakagari P, Breit A, Essin K, Gollasch M, Gudermann T (2008) Gq-coupled receptors as mechanosensors mediating myogenic vasoconstriction. EMBO J 27(23):3092–3103. doi:10.1038/emboj.2008.233

    PubMed  CAS  Google Scholar 

  • Meseguer V, Karashima Y, Talavera K, D’Hoedt D, Donovan-Rodriguez T, Viana F, Nilius B, Voets T (2008) Transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole. J Neurosci 28(3):576–586. doi:10.1523/JNEUROSCI.4772-07.2008

    PubMed  CAS  Google Scholar 

  • Miehe S, Crause P, Schmidt T, Lohn M, Kleemann HW, Licher T, Dittrich W, Rutten H, Strubing C (2012) Inhibition of diacylglycerol-sensitive TRPC channels by synthetic and natural steroids. PLoS One 7(4):e35393. doi:10.1371/journal.pone.0035393

    PubMed Central  PubMed  CAS  Google Scholar 

  • Millholland MG, Mishra S, Dupont CD, Love MS, Patel B, Shilling D, Kazanietz MG, Foskett JK, Hunter CA, Sinnis P, Greenbaum DC (2013) A host GPCR signaling network required for the cytolysis of infected cells facilitates release of apicomplexan parasites. Cell Host Microbe 13(1):15–28. doi:10.1016/j.chom.2012.12.001

    PubMed Central  PubMed  CAS  Google Scholar 

  • Molkentin JD, Dorn GW 2nd (2001) Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol 63:391–426. doi:10.1146/annurev.physiol.63.1.39163/1/391 [pii]

    PubMed  CAS  Google Scholar 

  • Moller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, Pippin JW, Rastaldi MP, Wawersik S, Schiavi S, Henger A, Kretzler M, Shankland SJ, Reiser J (2007) Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol 18(1):29–36. doi:10.1681/ASN.2006091010

    PubMed  CAS  Google Scholar 

  • Monet M, Francoeur N, Boulay G (2012) Involvement of phosphoinositide 3-kinase and PTEN protein in mechanism of activation of TRPC6 protein in vascular smooth muscle cells. J Biol Chem 287(21):17672–17681. doi:10.1074/jbc.M112.341354

    PubMed Central  PubMed  CAS  Google Scholar 

  • Mottl AK, Lu M, Fine CA, Weck KE (2013) A novel TRPC6 mutation in a family with podocytopathy and clinical variability. BMC Nephrol 14:104. doi:10.1186/1471-2369-14-104

    PubMed Central  PubMed  Google Scholar 

  • Muller M, Essin K, Hill K, Beschmann H, Rubant S, Schempp CM, Gollasch M, Boehncke WH, Harteneck C, Muller WE, Leuner K (2008) Specific TRPC6 channel activation, a novel approach to stimulate keratinocyte differentiation. J Biol Chem 283(49):33942–33954. doi:10.1074/jbc.M801844200

    PubMed Central  PubMed  Google Scholar 

  • Nishida M, Watanabe K, Sato Y, Nakaya M, Kitajima N, Ide T, Inoue R, Kurose H (2010) Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition. J Biol Chem 285(17):13244–13253. doi:10.1074/jbc.M109.074104

    PubMed Central  PubMed  CAS  Google Scholar 

  • Nishioka K, Nishida M, Ariyoshi M, Jian Z, Saiki S, Hirano M, Nakaya M, Sato Y, Kita S, Iwamoto T, Hirano K, Inoue R, Kurose H (2011) Cilostazol suppresses angiotensin II-induced vasoconstriction via protein kinase A-mediated phosphorylation of the transient receptor potential canonical 6 channel. Arterioscler Thromb Vasc Biol 31(10):2278–2286. doi:10.1161/ATVBAHA.110.221010

    PubMed  CAS  Google Scholar 

  • 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(39):27359–27370

    PubMed  CAS  Google Scholar 

  • Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y, Mori Y, Nagao T, Kurose H (2006) TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J 25(22):5305–5316. doi:10.1038/sj.emboj.7601417, 7601417 [pii]

    PubMed Central  PubMed  CAS  Google Scholar 

  • Owsianik G, D’Hoedt D, Voets T, Nilius B (2006) Structure-function relationship of the TRP channel superfamily. Rev Physiol Biochem Pharmacol 156:61–90

    PubMed  CAS  Google Scholar 

  • Ramanathan G, Gupta S, Thielmann I, Pleines I, Varga-Szabo D, May F, Mannhalter C, Dietrich A, Nieswandt B, Braun A (2012) Defective diacylglycerol-induced Ca2+ entry but normal agonist-induced activation responses in TRPC6-deficient mouse platelets. J Thromb Haemost 10(3):419–429. doi:10.1111/j.1538-7836.2011.04596.x

    PubMed  CAS  Google Scholar 

  • Redondo PC, Jardin I, Lopez JJ, Salido GM, Rosado JA (2008) Intracellular Ca2+ store depletion induces the formation of macromolecular complexes involving hTRPC1, hTRPC6, the type II IP3 receptor and SERCA3 in human platelets. Biochim Biophys Acta 1783(6):1163–1176. doi:10.1016/j.bbamcr.2007.12.008

    PubMed  CAS  Google Scholar 

  • 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(7):739–744. doi:10.1038/ng1592

    PubMed Central  PubMed  CAS  Google Scholar 

  • Samapati R, Yang Y, Yin J, Stoerger C, Arenz C, Dietrich A, Gudermann T, Adam D, Wu S, Freichel M, Flockerzi V, Uhlig S, Kuebler WM (2012) Lung endothelial Ca2+ and permeability response to platelet-activating factor is mediated by acid sphingomyelinase and transient receptor potential classical 6. Am J Respir Crit Care Med 185(2):160–170. doi:10.1164/rccm.201104-0717OC

    PubMed  CAS  Google Scholar 

  • Schlondorff J, Del Camino D, Carrasquillo R, Lacey V, Pollak MR (2009) TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. Am J Physiol Cell Physiol 296(3):C558–C569. doi:10.1152/ajpcell.00077.2008

    PubMed Central  PubMed  CAS  Google Scholar 

  • Sel S, Rost BR, Yildirim AO, Sel B, Kalwa H, Fehrenbach H, Renz H, Gudermann T, Dietrich A (2008) Loss of classical transient receptor potential 6 channel reduces allergic airway response. Clin Exp Allergy 38(9):1548–1558. doi:10.1111/j.1365-2222.2008.03043.x, CEA3043 [pii]

    PubMed  CAS  Google Scholar 

  • Sharif-Naeini R, Dedman A, Folgering JH, Duprat F, Patel A, Nilius B, Honore E (2008) TRP channels and mechanosensory transduction: insights into the arterial myogenic response. Pflugers Arch 456(3):529–540. doi:10.1007/s00424-007-0432-y

    PubMed  CAS  Google Scholar 

  • Shen B, Kwan HY, Ma X, Wong CO, Du J, Huang Y, Yao X (2011) cAMP activates TRPC6 channels via the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-mitogen-activated protein kinase kinase (MEK)-ERK1/2 signaling pathway. J Biol Chem 286(22):19439–19445. doi:10.1074/jbc.M110.210294

    PubMed Central  PubMed  CAS  Google Scholar 

  • 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(Pt 2):415–432. doi:10.1113/jphysiol.2004.075051

    PubMed Central  PubMed  CAS  Google Scholar 

  • Shi Y, Ding X, He ZH, Zhou KC, Wang Q, Wang YZ (2009) Critical role of TRPC6 channels in G2 phase transition and the development of human oesophageal cancer. Gut 58(11):1443–1450. doi:10.1136/gut.2009.181735

    PubMed  CAS  Google Scholar 

  • Shi J, Ju M, Saleh SN, Albert AP, Large WA (2010) TRPC6 channels stimulated by angiotensin II are inhibited by TRPC1/C5 channel activity through a Ca2 + - and PKC-dependent mechanism in native vascular myocytes. J Physiol 588(Pt 19):3671–3682. doi:10.1113/jphysiol.2010.194621

    PubMed Central  PubMed  CAS  Google Scholar 

  • Shi J, Geshi N, Takahashi S, Kiyonaka S, Ichikawa J, Hu Y, Mori Y, Ito Y, Inoue R (2013) Molecular determinants for cardiovascular TRPC6 channel regulation by Ca2+/calmodulin-dependent kinase II. J Physiol. doi:10.1113/jphysiol.2013.251249

    PubMed  Google Scholar 

  • Shlykov SG, Yang M, Alcorn JL, Sanborn BM (2003) Capacitative cation entry in human myometrial cells and augmentation by hTrpC3 overexpression. Biol Reprod 69(2):647–655. doi:10.1095/biolreprod.103.015396

    PubMed  CAS  Google Scholar 

  • Singh I, Knezevic N, Ahmmed GU, Kini V, Malik AB, Mehta D (2007) Galphaq-TRPC6-mediated Ca2+ entry induces RhoA activation and resultant endothelial cell shape change in response to thrombin. J Biol Chem 282(11):7833–7843

    PubMed  CAS  Google Scholar 

  • 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(48):39786–39794

    PubMed  CAS  Google Scholar 

  • Song J, Wang Y, Li X, Shen Y, Yin M, Guo Y, Diao L, Liu Y, Yue D (2013) Critical role of TRPC6 channels in the development of human renal cell carcinoma. Mol Biol Rep. doi:10.1007/s11033-013-2613-4

    Google Scholar 

  • Spassova MA, Soboloff J, He LP, Hewavitharana T, Xu W, Venkatachalam K, van Rossum DB, Patterson RL, Gill DL (2004) Calcium entry mediated by SOCs and TRP channels: variations and enigma. Biochim Biophys Acta 1742(1–3):9–20

    PubMed  CAS  Google Scholar 

  • Storch U, Forst AL, Philipp M, Gudermann T, Mederos y Schnitzler M (2012) Transient receptor potential channel 1 (TRPC1) reduces calcium permeability in heteromeric channel complexes. J Biol Chem 287(5):3530–3540. doi:10.1074/jbc.M111.283218

    PubMed Central  PubMed  CAS  Google Scholar 

  • Strubing C, Krapivinsky G, Krapivinsky L, Clapham DE (2003) Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem 278(40):39014–39019

    PubMed  Google Scholar 

  • Suchyna TM, Johnson JH, Hamer K, Leykam JF, Gage DA, Clemo HF, Baumgarten CM, Sachs F (2000) Identification of a peptide toxin from Grammostola spatulata spider venom that blocks cation-selective stretch-activated channels. J Gen Physiol 115(5):583–598

    PubMed Central  PubMed  CAS  Google Scholar 

  • Tai Y, Feng S, Ge R, Du W, Zhang X, He Z, Wang Y (2008) TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway. J Cell Sci 121(Pt 14):2301–2307. doi:10.1242/jcs.026906

    PubMed  CAS  Google Scholar 

  • Tai Y, Feng S, Du W, Wang Y (2009) Functional roles of TRPC channels in the developing brain. Pflugers Arch 458(2):283–289. doi:10.1007/s00424-008-0618-y

    PubMed  CAS  Google Scholar 

  • Takahashi S, Lin H, Geshi N, Mori Y, Kawarabayashi Y, Takami N, Mori MX, Honda A, Inoue R (2008) Nitric oxide-cGMP-protein kinase G pathway negatively regulates vascular transient receptor potential channel TRPC6. J Physiol 586(Pt 17):4209–4223. doi:10.1113/jphysiol.2008.156083

    PubMed Central  PubMed  CAS  Google Scholar 

  • Tauseef M, Knezevic N, Chava KR, Smith M, Sukriti S, Gianaris N, Obukhov AG, Vogel SM, Schraufnagel DE, Dietrich A, Birnbaumer L, Malik AB, Mehta D (2012) TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation. J Exp Med 209(11):1953–1968. doi:10.1084/jem.20111355

    PubMed Central  PubMed  CAS  Google Scholar 

  • Tesfai Y, Brereton HM, Barritt GJ (2001) A diacylglycerol-activated Ca2+ channel in PC12 cells (an adrenal chromaffin cell line) correlates with expression of the TRP-6 (transient receptor potential) protein. Biochem J 358(Pt 3):717–726

    PubMed Central  PubMed  CAS  Google Scholar 

  • 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, Skryma R, Prevarskaya N (2006) Differential role of transient receptor potential channels in Ca2+ entry and proliferation of prostate cancer epithelial cells. Cancer Res 66(4):2038–2047

    PubMed  CAS  Google Scholar 

  • Thilo F, Vorderwulbecke BJ, Marki A, Krueger K, Liu Y, Baumunk D, Zakrzewicz A, Tepel M (2012) Pulsatile atheroprone shear stress affects the expression of transient receptor potential channels in human endothelial cells. Hypertension 59(6):1232–1240. doi:10.1161/HYPERTENSIONAHA.111.183608

    PubMed  CAS  Google Scholar 

  • Tian D, Jacobo SM, Billing D, Rozkalne A, Gage SD, Anagnostou T, Pavenstadt H, Hsu HH, Schlondorff J, Ramos A, Greka A (2010) Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Sci Signal 3(145):ra77. doi:10.1126/scisignal.2001200

    PubMed Central  PubMed  Google Scholar 

  • 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(37):11701–11708. doi:10.1021/bi049349f

    PubMed  CAS  Google Scholar 

  • Tsvilovskyy VV, Zholos AV, Aberle T, Philipp SE, Dietrich A, Zhu MX, Birnbaumer L, Freichel M, Flockerzi V (2009) Deletion of TRPC4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo. Gastroenterology 137(4):1415–1424. doi:10.1053/j.gastro.2009.06.046

    PubMed Central  PubMed  Google Scholar 

  • Tu P, Gibon J, Bouron A (2010) The TRPC6 channel activator hyperforin induces the release of zinc and calcium from mitochondria. J Neurochem 112(1):204–213. doi:10.1111/j.1471-4159.2009.06446.x

    PubMed  CAS  Google Scholar 

  • Urban N, Hill K, Wang L, Kuebler WM, Schaefer M (2012) Novel pharmacological TRPC inhibitors block hypoxia-induced vasoconstriction. Cell Calcium 51(2):194–206. doi:10.1016/j.ceca.2012.01.001

    PubMed  CAS  Google Scholar 

  • van Rossum DB, Oberdick D, Rbaibi Y, Bhardwaj G, Barrow RK, Nikolaidis N, Snyder SH, Kiselyov K, Patterson RL (2008) TRP_2, a lipid/trafficking domain that mediates diacylglycerol-induced vesicle fusion. J Biol Chem 283(49):34384–34392. doi:10.1074/jbc.M804707200

    PubMed Central  PubMed  Google Scholar 

  • Varga-Szabo D, Braun A, Kleinschnitz C, Bender M, Pleines I, Pham M, Renne T, Stoll G, Nieswandt B (2008) The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J Exp Med 205(7):1583–1591. doi:10.1084/jem.20080302

    PubMed Central  PubMed  CAS  Google Scholar 

  • Wang J, Shimoda LA, Weigand L, Wang W, Sun D, Sylvester JT (2005) Acute hypoxia increases intracellular [Ca2+] in pulmonary arterial smooth muscle by enhancing capacitative Ca2+ entry. Am J Physiol Lung Cell Mol Physiol 288(6):L1059–L1069. doi:10.1152/ajplung.00448.2004

    PubMed  CAS  Google Scholar 

  • Wang J, Weigand L, Lu W, Sylvester JT, Semenza GL, Shimoda LA (2006) Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca2+ in pulmonary arterial smooth muscle cells. Circ Res 98(12):1528–1537. doi:10.1161/01.RES.0000227551.68124.98

    PubMed  CAS  Google Scholar 

  • Wang Y, Yue D, Li K, Liu YL, Ren CS, Wang P (2010) The role of TRPC6 in HGF-induced cell proliferation of human prostate cancer DU145 and PC3 cells. Asian J Androl 12(6):841–852. doi:10.1038/aja.2010.85

    PubMed Central  PubMed  CAS  Google Scholar 

  • Wang Y, Ding M, Chaudhari S, Ding Y, Yuan J, Stankowska D, He S, Krishnamoorthy R, Cunningham JT, Ma R (2013) Nuclear factor kappaB mediates suppression of canonical transient receptor potential 6 expression by reactive oxygen species and protein kinase C in kidney cells. J Biol Chem 288(18):12852–12865. doi:10.1074/jbc.M112.410357

    PubMed  CAS  Google Scholar 

  • Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, Olschewski A, Storch U, Mederos y Schnitzler M, Ghofrani HA, Schermuly RT, Pinkenburg O, Seeger W, Grimminger F, Gudermann T (2006) Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci USA 103(50):19093–19098

    PubMed Central  PubMed  CAS  Google Scholar 

  • Weissmann N, Sydykov A, Kalwa H, Storch U, Fuchs B, Mederos y Schnitzler M, Brandes RP, Grimminger F, Meissner M, Freichel M, Offermanns S, Veit F, Pak O, Krause KH, Schermuly RT, Brewer AC, Schmidt HH, Seeger W, Shah AM, Gudermann T, Ghofrani HA, Dietrich A (2012) Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice. Nat Commun 3:649. doi:10.1038/ncomms1660

    PubMed Central  PubMed  Google Scholar 

  • Welsh DG, Morielli AD, Nelson MT, Brayden JE (2002) Transient receptor potential channels regulate myogenic tone of resistance arteries. Circ Res 90(3):248–250

    PubMed  CAS  Google Scholar 

  • 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(5729):1801–1804

    PubMed  CAS  Google Scholar 

  • Woelfle U, Laszczyk MN, Kraus M, Leuner K, Kersten A, Simon-Haarhaus B, Scheffler A, Martin SF, Muller WE, Nashan D, Schempp CM (2010) Triterpenes promote keratinocyte differentiation in vitro, ex vivo and in vivo: a role for the transient receptor potential canonical (subtype) 6. J Invest Dermatol 130(1):113–123. doi:10.1038/jid.2009.248

    PubMed  CAS  Google Scholar 

  • Xie J, Cha SK, An SW, Kuro OM, Birnbaumer L, Huang CL (2012) Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun 3:1238. doi:10.1038/ncomms2240

    PubMed Central  PubMed  Google Scholar 

  • 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(2):C316–C330

    PubMed  CAS  Google Scholar 

  • 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 USA 101(38):13861–13866

    PubMed Central  PubMed  CAS  Google Scholar 

  • Yu Y, Keller SH, Remillard CV, Safrina O, Nicholson A, Zhang SL, Jiang W, Vangala N, Landsberg JW, Wang JY, Thistlethwaite PA, Channick RN, Robbins IM, Loyd JE, Ghofrani HA, Grimminger F, Schermuly RT, Cahalan MD, Rubin LJ, Yuan JX (2009) A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation 119(17):2313–2322. doi:10.1161/CIRCULATIONAHA.108.782458

    PubMed Central  PubMed  CAS  Google Scholar 

  • Yuan JP, Zeng W, Huang GN, Worley PF, Muallem S (2007) STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat Cell Biol 9(6):636–645. doi:10.1038/ncb1590

    PubMed Central  PubMed  CAS  Google Scholar 

  • Yuan JP, Kim MS, Zeng W, Shin DM, Huang G, Worley PF, Muallem S (2009) TRPC channels as STIM1-regulated SOCs. Channels (Austin) 3(4):221–225, 9198 [pii]

    CAS  Google Scholar 

  • Zhang L, Saffen D (2001) Muscarinic acetylcholine receptor regulation of TRP6 Ca2+ channel isoforms. Molecular structures and functional characterization. J Biol Chem 276(16):13331–13339

    PubMed  CAS  Google Scholar 

  • 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 USA 98(6):3168–3173. doi:10.1073/pnas.051632698

    PubMed Central  PubMed  CAS  Google Scholar 

  • Zhang SL, Kozak JA, Jiang W, Yeromin AV, Chen J, Yu Y, Penna A, Shen W, Chi V, Cahalan MD (2008) Store-dependent and -independent modes regulating Ca2+ release-activated Ca2+ channel activity of human Orai1 and Orai3. J Biol Chem 283(25):17662–17671. doi:10.1074/jbc.M801536200

    PubMed Central  PubMed  CAS  Google Scholar 

  • Zhang J, Pippin JW, Vaughan MR, Krofft RD, Taniguchi Y, Romagnani P, Nelson PJ, Liu ZH, Shankland SJ (2012) Retinoids augment the expression of podocyte proteins by glomerular parietal epithelial cells in experimental glomerular disease. Nephron Exp Nephrol 121(1–2):e23–e37. doi:10.1159.00034.8.8

    PubMed Central  PubMed  CAS  Google Scholar 

  • Zhang SS, Wen J, Yang F, Cai XL, Yang H, Luo KJ, Liu QW, Hu RG, Xie X, Huang QY, Chen JY, Fu JH, Hu Y (2013) High expression of Transient potential receptor C6 correlated with poor prognosis in patients with esophageal squamous cell carcinoma. Med Oncol 30(3):607. doi:10.1007/s12032-013-0607-7

    PubMed  Google Scholar 

  • Zhou J, Du W, Zhou K, Tai Y, Yao H, Jia Y, Ding Y, Wang Y (2008) Critical role of TRPC6 channels in the formation of excitatory synapses. Nat Neurosci 11(7):741–743. doi:10.1038/nn.2127

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alexander Dietrich .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Dietrich, A., Gudermann, T. (2014). TRPC6: Physiological Function and Pathophysiological Relevance. In: Nilius, B., Flockerzi, V. (eds) Mammalian Transient Receptor Potential (TRP) Cation Channels. Handbook of Experimental Pharmacology, vol 222. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54215-2_7

Download citation

Publish with us

Policies and ethics