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Gene Review

TRPC6  -  transient receptor potential cation...

Homo sapiens

Synonyms: FSGS2, Short transient receptor potential channel 6, TRP-6, TRP6, Transient receptor protein 6, ...
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Disease relevance of TRPC6

  • TRPC6 likely contributes to receptor-operated and mechanosensitive Ca2+ mobilizations, being involved in vasoconstrictor and myogenic responses and pulmonary arterial proliferation and its associated disease (idiopathic pulmonary arterial hypertension) [1].
  • Lastly, TRPC6 coimmunoprecipitated with the NKA pump when the proteins were coexpressed in Spodoptera frugiperda insect cells using recombinant baculoviruses [2].
  • Cardiac-specific overexpression of TRPC6 in transgenic mice resulted in heightened sensitivity to stress, a propensity for lethal cardiac growth and heart failure, and an increase in NFAT-dependent expression of beta-myosin heavy chain, a sensitive marker for pathologic hypertrophy [3].
  • TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy [4].
  • In both WT and TRPC6(-/-) PASMC hypoxia caused diacylglycerol (DAG) accumulation [5].

Psychiatry related information on TRPC6

  • In conclusion, the present study suggests that the LPC, a major component of oxidized low-density lipoprotiens, increases calcium in corporal smooth muscle cells probably through activation of a TRPC6 channel and the increased [Ca2+]i by LPC via TRP channels is one of mechanisms for hypercholesterolemia-induced erectile dysfunction [6].

High impact information on TRPC6

  • Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm [7].
  • We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q [7].
  • Although hTRPC3, the closest structural relative of hTRPC6, is activated in the same way, TRPCs 1, 4 and 5 and the vanilloid receptor subtype 1 are unresponsive to the lipid mediator [8].
  • The mechanosensing properties of TRPC6 channels highly expressed in smooth muscle cells are likely to play a key role in regulating myogenic tone in vascular tissue [9].
  • TRPC6 is a receptor-activated nonselective cation channel expressed widely in vascular smooth muscle and other cell types [9].

Biological context of TRPC6


Anatomical context of TRPC6


Associations of TRPC6 with chemical compounds

  • In phosphorylation studies, we report that neither TRPC6 nor TRPC1 was a substrate for tyrosine kinases [10].
  • Using Fura-2-loaded platelets, we report that, in line with TRPC6 expression, 1-oleoyl-2-acetyl-sn-glycerol (OAG) stimulated the entry of Ca(++) and Ba(2+) independently of protein kinase C. Thrombin also induced the entry of Ca(++) and Ba(2+), but thapsigargin, which depletes the stores, induced the entry of only Ca(++) [10].
  • In contrast, 2APB inhibits the activity of TRPC6 and TRPM8 evoked by 1-oleolyl-2-acetyl-sn-glycerol and menthol, respectively [18].
  • The PIP(3)-activated Ca(2+) entry is inhibited by known TRPC6 inhibitors such as Gd(3+) and SKF96365 and is independent of IP(3) production [11].
  • Although the activating effect of PIP(3) on TRPC6 is reminiscent to that of 1-oleoyl-2-acetyl-sn-glycerol, this activation is not attributable to the diacylglycerol substructure of PIP(3) since other phosphoinositides failed to trigger Ca(2+) responses [11].
  • TRPC6 bound directly to PIs, and with highest potency to phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) [19].
  • TRPC6 activation by hyperforin may represent a new innovative therapeutic strategy in skin disorders characterized by altered keratinocyte differentiation [20].

Physical interactions of TRPC6

  • Using a yeast two-hybrid interaction assay, we found that the second ankyrin-like repeat domain of TRPC6 interacted with MxA, a member of the dynamin superfamily [21].

Regulatory relationships of TRPC6

  • Flufenamic acid, which has been shown to enhance activity of TRPC-6 but inhibit TRPC-3 and -7, enhanced the VEGF-mediated increase in L(p) in approximately half of the vessels tested but inhibited the response in the other half of the vessels [22].
  • These results suggest that PDGF-mediated PASMC proliferation is associated with c-Jun/STAT3-induced upregulation of TRPC6 expression [23].
  • TRPC6 is thought to be a Ca(2+)-permeable cation channel activated following stimulation of G-protein-coupled membrane receptors linked to phospholipase C (PLC) [24].

Other interactions of TRPC6

  • Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol [8].
  • After dilatation, TRPC1 and TRPC6 mRNA were progressively increased compared with undilated control segments [13].
  • These data indicate a role for TRPC6- and/or TRPC7-containing channels and rule a more complex subunit composition including TRPC1 and TRPC4 [25].
  • The amplitude of arginine vasopressin (AVP)-induced ROC current was suppressed by dominant-negative mutant TRPC6 (TRPC6(DN)) but not TRPC5 (TRPC5(DN)) mutant subunit expression [25].
  • GTP binding-defective MxA mutants had only a minor potentiating effect on OAG-induced TRPC6 activity [21].

Analytical, diagnostic and therapeutic context of TRPC6


  1. Transient receptor potential channels in cardiovascular function and disease. Inoue, R., Jensen, L.J., Shi, J., Morita, H., Nishida, M., Honda, A., Ito, Y. Circ. Res. (2006) [Pubmed]
  2. Proteomic analysis of TRPC5- and TRPC6-binding partners reveals interaction with the plasmalemmal Na(+)/K(+)-ATPase. Goel, M., Sinkins, W., Keightley, A., Kinter, M., Schilling, W.P. Pflugers Arch. (2005) [Pubmed]
  3. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. Kuwahara, K., Wang, Y., McAnally, J., Richardson, J.A., Bassel-Duby, R., Hill, J.A., Olson, E.N. J. Clin. Invest. (2006) [Pubmed]
  4. TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. Onohara, N., Nishida, M., Inoue, R., Kobayashi, H., Sumimoto, H., Sato, Y., Mori, Y., Nagao, T., Kurose, H. EMBO J. (2006) [Pubmed]
  5. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Weissmann, N., Dietrich, A., Fuchs, B., Kalwa, H., Ay, M., Dumitrascu, R., Olschewski, A., Storch, U., Mederos Y Schnitzler, M., Ghofrani, H.A., Schermuly, R.T., Pinkenburg, O., Seeger, W., Grimminger, F., Gudermann, T. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  6. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces the change of calcium mobilization via TRPC ion channels in cultured human corporal smooth muscle cells. So, I., Chae, M.R., Kim, S.J., Lee, S.W. Int. J. Impot. Res. (2005) [Pubmed]
  7. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Reiser, J., Polu, K.R., Möller, C.C., Kenlan, P., Altintas, M.M., Wei, C., Faul, C., Herbert, S., Villegas, I., Avila-Casado, C., McGee, M., Sugimoto, H., Brown, D., Kalluri, R., Mundel, P., Smith, P.L., Clapham, D.E., Pollak, M.R. Nat. Genet. (2005) [Pubmed]
  8. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Hofmann, T., Obukhov, A.G., Schaefer, M., Harteneck, C., Gudermann, T., Schultz, G. Nature (1999) [Pubmed]
  9. A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Spassova, M.A., Hewavitharana, T., Xu, W., Soboloff, J., Gill, D.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. Expression and role of TRPC proteins in human platelets: evidence that TRPC6 forms the store-independent calcium entry channel. Hassock, S.R., Zhu, M.X., Trost, C., Flockerzi, V., Authi, K.S. Blood (2002) [Pubmed]
  11. The canonical transient receptor potential 6 channel as a putative phosphatidylinositol 3,4,5-trisphosphate-sensitive calcium entry system. Tseng, P.H., Lin, H.P., Hu, H., Wang, C., Zhu, M.X., Chen, C.S. Biochemistry (2004) [Pubmed]
  12. Store-operated Ca2+ entry in first trimester and term human placenta. Clarson, L.H., Roberts, V.H., Hamark, B., Elliott, A.C., Powell, T. J. Physiol. (Lond.) (2003) [Pubmed]
  13. Plasticity of TRPC expression in arterial smooth muscle: correlation with store-operated Ca2+ entry. Bergdahl, A., Gomez, M.F., Wihlborg, A.K., Erlinge, D., Eyjolfson, A., Xu, S.Z., Beech, D.J., Dreja, K., Hellstrand, P. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  14. Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Yu, Y., Fantozzi, I., Remillard, C.V., Landsberg, J.W., Kunichika, N., Platoshyn, O., Tigno, D.D., Thistlethwaite, P.A., Rubin, L.J., Yuan, J.X. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  15. mRNA distribution analysis of human TRPC family in CNS and peripheral tissues. Riccio, A., Medhurst, A.D., Mattei, C., Kelsell, R.E., Calver, A.R., Randall, A.D., Benham, C.D., Pangalos, M.N. Brain Res. Mol. Brain Res. (2002) [Pubmed]
  16. Exocytotic insertion of TRPC6 channel into the plasma membrane upon Gq protein-coupled receptor activation. Cayouette, S., Lussier, M.P., Mathieu, E.L., Bousquet, S.M., Boulay, G. J. Biol. Chem. (2004) [Pubmed]
  17. Apical localization of a functional TRPC3/TRPC6-Ca2+-signaling complex in polarized epithelial cells. Role in apical Ca2+ influx. Bandyopadhyay, B.C., Swaim, W.D., Liu, X., Redman, R.S., Patterson, R.L., Ambudkar, I.S. J. Biol. Chem. (2005) [Pubmed]
  18. 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. Hu, H.Z., Gu, Q., Wang, C., Colton, C.K., Tang, J., Kinoshita-Kawada, M., Lee, L.Y., Wood, J.D., Zhu, M.X. J. Biol. Chem. (2004) [Pubmed]
  19. Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6. Kwon, Y., Hofmann, T., Montell, C. Mol. Cell (2007) [Pubmed]
  20. Specific TRPC6 channel activation, a novel approach to stimulate keratinocyte differentiation. Müller, M., Essin, K., Hill, K., Beschmann, H., Rubant, S., Schempp, C.M., Gollasch, M., Boehncke, W.H., Harteneck, C., Müller, W.E., Leuner, K. J. Biol. Chem. (2008) [Pubmed]
  21. MxA, a member of the dynamin superfamily, interacts with the ankyrin-like repeat domain of TRPC. Lussier, M.P., Cayouette, S., Lepage, P.K., Bernier, C.L., Francoeur, N., St-Hilaire, M., Pinard, M., Boulay, G. J. Biol. Chem. (2005) [Pubmed]
  22. Evidence of a role for TRPC channels in VEGF-mediated increased vascular permeability in vivo. Pocock, T.M., Foster, R.R., Bates, D.O. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  23. PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Yu, Y., Sweeney, M., Zhang, S., Platoshyn, O., Landsberg, J., Rothman, A., Yuan, J.X. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  24. Human TRPC6 expressed in HEK 293 cells forms non-selective cation channels with limited Ca2+ permeability. Estacion, M., Sinkins, W.G., Jones, S.W., Applegate, M.A., Schilling, W.P. J. Physiol. (Lond.) (2006) [Pubmed]
  25. Heteromultimeric TRPC6-TRPC7 channels contribute to arginine vasopressin-induced cation current of A7r5 vascular smooth muscle cells. Maruyama, Y., Nakanishi, Y., Walsh, E.J., Wilson, D.P., Welsh, D.G., Cole, W.C. Circ. Res. (2006) [Pubmed]
  26. Expression of transient receptor potential C6 and related transient receptor potential family members in human airway smooth muscle and lung tissue. Corteling, R.L., Li, S., Giddings, J., Westwick, J., Poll, C., Hall, I.P. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]
  27. Physiological induction of transient receptor potential canonical proteins, calcium entry channels, in human myometrium: influence of pregnancy, labor, and interleukin-1 beta. Dalrymple, A., Slater, D.M., Poston, L., Tribe, R.M. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
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