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Gene Review

TRPC4  -  transient receptor potential cation...

Homo sapiens

Synonyms: HTRP-4, HTRP4, Short transient receptor potential channel 4, TRP4, Trp-related protein 4, ...
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Disease relevance of TRPC4

  • These results suggest that platelet CCE channel complexes contain TRPC4 as a molecular component that determines sensitivity of CCE to intracellular alkalosis [1].
  • The increases of CCE amplitude and ISOC current density by hypoxia were paralleled by enhanced TRPC4 mRNA and protein expression [2].

High impact information on TRPC4

  • 4) Expression of dominant-negative TRPC4 proteins suppressed TRPC3-related channel activity in the HEK293 expression system and in native endothelial cells [3].
  • To identify them, we generated chimeras by swapping the different domains of TRPC4 with the same regions in TRPC6 [4].
  • However, chimeras containing only the ankyrin repeats or only the coiled-coil domain of TRPC4 did not coimmunoprecipitate with TRPC4 [4].
  • Expression of antisense TRPC1 decreased (i) Tg- and OAG-stimulated currents and Ca2+ entry and (ii) the level of endogenous TRPC1 but not TRPC4 [5].
  • We report that two tyrosine residues in the C terminus of human TRPC4 (hTRPC4), Tyr-959 and Tyr-972, are phosphorylated following epidermal growth factor (EGF) receptor stimulation of COS-7 cells [6].

Biological context of TRPC4


Anatomical context of TRPC4


Associations of TRPC4 with chemical compounds

  • Unlike most other TRP-related channels, which are inhibited by La(3+) and Gd(3+), currents through TRPC4 and TRPC5 are potentiated by La(3+) [15].
  • TRPC3 and TRPC4 are activated by oxidants, which induce Na(+) and Ca(2+) entry into cells through mechanisms that are dependent on phospholipase C. TRPM2 is activated by oxidative stress or TNFalpha, and the mechanism involves production of ADP-ribose, which binds to an ADP-ribose binding cleft in the TRPM2 C-terminus [16].
  • Over-expression of TRPC4 in HEK293 cells was found to result in a gain of pH-sensitivity of CCE with clearly detectable promotion of CCE in response to monensin [1].
  • Alternative splice variants of hTrp4 differentially interact with the C-terminal portion of the inositol 1,4,5-trisphosphate receptors [17].
  • A similar distribution was observed in fundal myometrium samples from patients before and after the onset of labor. hTrpC4 mRNA was significantly lower after the onset of labor; there were no significant changes in the concentrations of other TrpC mRNAs [18].

Physical interactions of TRPC4

  • Using GST fusion proteins, we found that TRPC4 interacted with the PDZ1 domain of ZO-1 and that this was also dependent on the TRL motif [10].
  • Protein 4.1 interacts with TRPC4 and the membrane skeleton [19].

Co-localisations of TRPC4

  • Canonical transient receptor potential channel 4 (TRPC4) co-localizes with the scaffolding protein ZO-1 in human fetal astrocytes in culture [10].

Regulatory relationships of TRPC4


Other interactions of TRPC4

  • Knockdown of the level of endogenous TRPC1 or TRPC4 inhibited store-operated calcium entry, indicating they are part of the native SOC [21].
  • In all of these cells, hTrpC1 and hTrpC4 mRNAs were the most abundant, followed by hTrpC6 [18].
  • The functional effects of EBP50 on TRPC4/5 activity have not been investigated [22].
  • There is good evidence that it can heteromultimerise with the related proteins TRPC4, TRPC5 and polycystin-2; a tetrameric arrangement is envisaged, but not demonstrated [23].
  • In addition, TRPC4-/- mouse-lung endothelial cells exhibited lack of actin-stress fiber formation and cell retraction in response to thrombin activation of protease-activated receptor-1 (PAR-1) in endothelial cells [20].

Analytical, diagnostic and therapeutic context of TRPC4

  • Immunoprecipitation of TRPC1 pulled down TRPC3 but not TRPC4 [5].
  • In isolated-perfused mouse lungs, the PAR-1 agonist peptide increased microvessel filtration coefficient (K(f,c)), a measure of vascular permeability, by a factor of 2.8 in wt and 1.4 in TRPC4(-/-); La3+ (1 micromol/L) addition to wt lung perfusate reduced the agonist effect to that observed in TRPC4(-/-) [9].
  • Using a yeast two-hybrid assay and glutathione-S-transferase-pulldown experiments, we found that the C-terminus of alpha-hTrp4, but not of beta-hTrp4, associates in vitro with the C-terminal domain of the InsP(3) receptors type 1, 2 and 3 [17].
  • Members of the transient receptor potential (TRP) family of nonselective cation channels, TRPC1, TRPC4, and TRPC6, were detected by reverse transcription-polymerase chain reaction and Western blot in both A7r5 cells and MASMC [24].
  • Using a RT-PCR technique, a novel isoform of TRPC4, designated rTRPC4gamma, was isolated [25].


  1. TRPC4 expression determines sensitivity of the platelet-type capacitative Ca2+ entry channel to intracellular alkalosis. Wakabayashi, I., Marumo, M., Graziani, A., Poteser, M., Groschner, K. Platelets (2006) [Pubmed]
  2. Hypoxia increases AP-1 binding activity by enhancing capacitative Ca2+ entry in human pulmonary artery endothelial cells. Fantozzi, I., Zhang, S., Platoshyn, O., Remillard, C.V., Cowling, R.T., Yuan, J.X. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
  3. TRPC3 and TRPC4 Associate to Form a Redox-sensitive Cation Channel: EVIDENCE FOR EXPRESSION OF NATIVE TRPC3-TRPC4 HETEROMERIC CHANNELS IN ENDOTHELIAL CELLS. Poteser, M., Graziani, A., Rosker, C., Eder, P., Derler, I., Kahr, H., Zhu, M.X., Romanin, C., Groschner, K. J. Biol. Chem. (2006) [Pubmed]
  4. Identification of two domains involved in the assembly of transient receptor potential canonical channels. Lepage, P.K., Lussier, M.P., Barajas-Martinez, H., Bousquet, S.M., Blanchard, A.P., Francoeur, N., Dumaine, R., Boulay, G. J. Biol. Chem. (2006) [Pubmed]
  5. Molecular analysis of a store-operated and 2-acetyl-sn-glycerol-sensitive non-selective cation channel. Heteromeric assembly of TRPC1-TRPC3. Liu, X., Bandyopadhyay, B.C., Singh, B.B., Groschner, K., Ambudkar, I.S. J. Biol. Chem. (2005) [Pubmed]
  6. Epidermal growth factor induces tyrosine phosphorylation, membrane insertion, and activation of transient receptor potential channel 4. Odell, A.F., Scott, J.L., Van Helden, D.F. J. Biol. Chem. (2005) [Pubmed]
  7. 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]
  8. Transient receptor potential channels in endothelium: solving the calcium entry puzzle? Nilius, B., Droogmans, G., Wondergem, R. Endothelium (2003) [Pubmed]
  9. Impairment of store-operated Ca2+ entry in TRPC4(-/-) mice interferes with increase in lung microvascular permeability. Tiruppathi, C., Freichel, M., Vogel, S.M., Paria, B.C., Mehta, D., Flockerzi, V., Malik, A.B. Circ. Res. (2002) [Pubmed]
  10. Canonical transient receptor potential channel 4 (TRPC4) co-localizes with the scaffolding protein ZO-1 in human fetal astrocytes in culture. Song, X., Zhao, Y., Narcisse, L., Duffy, H., Kress, Y., Lee, S., Brosnan, C.F. Glia (2005) [Pubmed]
  11. Cytoskeletal reorganization internalizes multiple transient receptor potential channels and blocks calcium entry into human neutrophils. Itagaki, K., Kannan, K.B., Singh, B.B., Hauser, C.J. J. Immunol. (2004) [Pubmed]
  12. Transient receptor potential protein subunit assembly and membrane distribution in human platelets. Brownlow, S.L., Sage, S.O. Thromb. Haemost. (2005) [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. 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]
  15. Lanthanides potentiate TRPC5 currents by an action at extracellular sites close to the pore mouth. Jung, S., Mühle, A., Schaefer, M., Strotmann, R., Schultz, G., Plant, T.D. J. Biol. Chem. (2003) [Pubmed]
  16. The role of TRP channels in oxidative stress-induced cell death. Miller, B.A. J. Membr. Biol. (2006) [Pubmed]
  17. Alternative splice variants of hTrp4 differentially interact with the C-terminal portion of the inositol 1,4,5-trisphosphate receptors. Mery, L., Magnino, F., Schmidt, K., Krause, K.H., Dufour, J.F. FEBS Lett. (2001) [Pubmed]
  18. Expression of transient receptor channel proteins in human fundal myometrium in pregnancy. Ku, C.Y., Babich, L., Word, R.A., Zhong, M., Ulloa, A., Monga, M., Sanborn, B.M. J. Soc. Gynecol. Investig. (2006) [Pubmed]
  19. Activation of the endothelial store-operated ISOC Ca2+ channel requires interaction of protein 4.1 with TRPC4. Cioffi, D.L., Wu, S., Alexeyev, M., Goodman, S.R., Zhu, M.X., Stevens, T. Circ. Res. (2005) [Pubmed]
  20. Ca2+ Signaling, TRP Channels, and Endothelial Permeability. Tiruppathi, C., Ahmmed, G.U., Vogel, S.M., Malik, A.B. Microcirculation (New York, N.Y. : 1994) (2006) [Pubmed]
  21. Phospholipase cgamma1 is required for activation of store-operated channels in human keratinocytes. Tu, C.L., Chang, W., Bikle, D.D. J. Invest. Dermatol. (2005) [Pubmed]
  22. TRPC5 activation kinetics are modulated by the scaffolding protein ezrin/radixin/moesin-binding phosphoprotein-50 (EBP50). Obukhov, A.G., Nowycky, M.C. J. Cell. Physiol. (2004) [Pubmed]
  23. TRPC1 store-operated cationic channel subunit. Beech, D.J., Xu, S.Z., McHugh, D., Flemming, R. Cell Calcium (2003) [Pubmed]
  24. Pharmacological and electrophysiological characterization of store-operated currents and capacitative Ca2+ entry in vascular smooth muscle cells. Brueggemann, L.I., Markun, D.R., Henderson, K.K., Cribbs, L.L., Byron, K.L. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  25. Cloning and functional expression of a novel splice variant of rat TRPC4. Satoh, E., Ono, K., Xu, F., Iijima, T. Circ. J. (2002) [Pubmed]
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