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Gene Review

TRPV5  -  transient receptor potential cation...

Homo sapiens

Synonyms: CAT2, CaT2, Calcium transport protein 2, ECAC1, ECaC, ...
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Disease relevance of TRPV5

  • The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption [1].
  • In contrast, metabolic acidosis did not affect Ca2+ excretion in TRPV5 knockout (TRPV5-/-) mice, in which active Ca2+ reabsorption is effectively abolished [2].
  • WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4 [3].
  • Furthermore, TRPV5 deficiency in mice is associated with polyuria, urine acidification, and reduced bone thickness [4].
  • LPMC present in abnormal segments from 71% of patients with chronic inflammatory bowel disease were cytotoxic for ECAC isolated from colon (12.5 +/- 8.9% specific lysis) and small bowel (7.1 +/- 6.5%), but not for kidney control antigen (0.8 +/- 1.1%) isolated in a manner analogous to that used for ECAC (P less than 0.02) [5].

High impact information on TRPV5

  • A major breakthrough in completing the molecular details of these pathways was the identification of the epithelial Ca(2+) channel family consisting of two members: TRPV5 and TRPV6 [6].
  • Second, HCTZ administration still induced hypocalciuria in transient receptor potential channel subfamily V, member 5-knockout (Trpv5-knockout) mice, in which active distal Ca2+ reabsorption is abolished due to inactivation of the epithelial Ca2+ channel Trpv5 [7].
  • Expression of ECAC was found by immunofluorescence using characterized oligo-specific or monoclonal antibody: tamarin intestinal epithelium--but not lamina propria, muscularis mucosae, subserosa, or glycocalyx--demonstrated determinants of the ECAC antigen system [8].
  • Furthermore, coded sera from 10 tamarins with biopsy-proven inflammation involving colonic intestinal mucosa and in which disease activity was moderate to severe showed ECAC-specific cytotoxicity of 3.6% +/- 1.6% [8].
  • To explore one putative immunopathogenic pathway for the chronic colitis, we determined whether immune sensitization to macromolecules associated with mucosal epithelium of intestine (designated ECAC) had occurred in this primate species [8].

Chemical compound and disease context of TRPV5


Biological context of TRPV5

  • The experiments demonstrate the significance of SGK1 and NHERF2 as TRPV5 modulators which are likely to participate in the regulation of calcium homeostasis by 1,25(OH)2D3 [12].
  • Only one ECaC gene seems to exist in the F. rubripes genome, and the corresponding protein clusters together with ECaC2 from mammals upon phylogenetic analysis [13].
  • Importantly, downregulation of annexin 2 using annexin 2-specific small interfering RNA inhibited TRPV5 and TRPV6-mediated currents in transfected HEK293 cells [14].
  • Here, we demonstrate using protein-binding analysis, subcellular fractionation and evanescent-field microscopy that CaBP(28K) translocates towards the plasma membrane and directly associates with TRPV5 at a low [Ca(2+)](i) [15].
  • This S100 protein forms a heterotetrameric complex with annexin 2 and associates specifically with the conserved sequence VATTV located in the C-terminal tail of TRPV5 and TRPV6 [14].

Anatomical context of TRPV5


Associations of TRPV5 with chemical compounds

  • Ba(2+) total patch currents were consistently blocked by addition of NiCl(2), Nifedipine (L-type voltage-gated calcium channel blocker) or Ruthenium Red (TRPV5-TRPV6 channel blocker); Nifedipine and Ruthenium Red exerted a synergic blocking effect on Ba(2+) total patch currents [17].
  • Regulation of the epithelial Ca2+ channels TRPV5 and TRPV6 by 1alpha,25-dihydroxy Vitamin D3 and dietary Ca2+ [18].
  • The mRNA levels of renal 25-hydoxyvitamin D 24-hydroxylase (24OHase) increased, whereas those of renal 25-hydroxyvitamin D 1-alpha hydroxylase (1alpha-hydroxylase), duodenal transient receptor potential cation channel, subfamily V, member 6 (TRPV6), TRPV5, and calbindin-D9k were all decreased [19].
  • A glycosylation site in the first extracellular loop of TRPV5 is enzymatically cleaved by a secreted glucuronidase, indirectly regulating channel function [20].
  • The epithelial calcium channels, TRPV5 and TRPV6, have been extensively studied in epithelial tissues controlling the Ca(2+) homeostasis and exhibit a range of distinctive properties that distinguish them from other TRP channels [21].

Physical interactions of TRPV5

  • Pull-down experiments and overlay assays revealed that the TRPV5 C-tail interacts in a Ca2+-independent manner with NHERF2 [12].
  • ECaC constitutes the rate-limiting apical entry step in the process of active transcellular Ca(2+) transport and belongs to a superfamily of Ca(2+) channels that includes the vanilloid receptor and transient receptor potential channels [22].
  • Klotho stabilizes the TRPV5 Ca2+ channel in the plasma membrane by deglycosylation of the protein [23].
  • The identification of the epithelial Ca(2+) channel (ECaC) complements the group of Ca(2+) transport proteins including calbindin-D28K, Na(+)/Ca(2+) exchanger and plasma membrane Ca(2+)-ATPase, which are co-expressed in 1,25(OH)2D3- responsive nephron segments [22].

Regulatory relationships of TRPV5

  • The mRNA for CaT1 was expressed more abundantly than that for CaT2 in three major tissues involved in transcellular calcium transport, namely intestine, kidney, and placenta, as determined by quantitative PCR [24].
  • As shown recently, TRPV5 is activated by the serum and glucocorticoid inducible kinase SGK1, a kinase transcriptionally upregulated by 1,25(OH)2D3 [12].
  • Calbindin-D28K dynamically controls TRPV5-mediated Ca2+ transport [15].
  • Moreover, the molecular mechanism by which the antiaging hormone Klotho regulates TRPV5 activity may prove to be generally applicable in Klotho-mediated prevention of aging [23].
  • The immunophilin FKBP52 inhibits the activity of the epithelial Ca2+ channel TRPV5 [25].

Other interactions of TRPV5

  • Within the TRPV subgroup, TRPV5 and TRPV6 show exclusive calcium selectivity and play an important role in calcium uptake [26].
  • Coexpression of TRPV5 with both (S422D)SGK1 and NHERF2 stimulates tracer Ca2+ entry, ICa and ICl(Ca) [27].
  • The present study aims to define the molecular requirements for the interaction of TRPV5 with SGK1 and NHERF2 [12].
  • Using GST pull-down and co-immunoprecipitation assays we demonstrated that annexin 2 is part of the TRPV5-S100A10 complex [14].
  • When the thiazide-sensitive Na(+)-Cl(-) cotransporter NCC was coexpressed, the effect of WNK4 on TRPV5 was weakened by NCC in a dose-dependent manner [3].

Analytical, diagnostic and therapeutic context of TRPV5


  1. The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption. van der Eerden, B.C., Hoenderop, J.G., de Vries, T.J., Schoenmaker, T., Buurman, C.J., Uitterlinden, A.G., Pols, H.A., Bindels, R.J., van Leeuwen, J.P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Acid-base status determines the renal expression of Ca2+ and Mg2+ transport proteins. Nijenhuis, T., Renkema, K.Y., Hoenderop, J.G., Bindels, R.J. J. Am. Soc. Nephrol. (2006) [Pubmed]
  3. WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4. Jiang, Y., Ferguson, W.B., Peng, J.B. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  4. TRPV5, the gateway to Ca2+ homeostasis. Mensenkamp, A.R., Hoenderop, J.G., Bindels, R.J. Handbook of experimental pharmacology (2007) [Pubmed]
  5. Sensitization to epithelial antigens in chronic mucosal inflammatory disease. Characterization of human intestinal mucosa-derived mononuclear cells reactive with purified epithelial cell-associated components in vitro. Roche, J.K., Fiocchi, C., Youngman, K. J. Clin. Invest. (1985) [Pubmed]
  6. Calcium absorption across epithelia. Hoenderop, J.G., Nilius, B., Bindels, R.J. Physiol. Rev. (2005) [Pubmed]
  7. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. Nijenhuis, T., Vallon, V., van der Kemp, A.W., Loffing, J., Hoenderop, J.G., Bindels, R.J. J. Clin. Invest. (2005) [Pubmed]
  8. Expression of immune sensitization to epithelial cell-associated components in the cotton-top tamarin: a model of chronic ulcerative colitis. Winter, H.S., Crum, P.M., King, N.W., Sehgal, P.K., Roche, J.K. Gastroenterology (1989) [Pubmed]
  9. Platonin attenuates LPS-induced CAT-2 and CAT-2B induction in stimulated murine macrophages. Chen, C.C., Lee, J.J., Tsai, P.S., Lu, Y.T., Huang, C.L., Huang, C.J. Acta anaesthesiologica Scandinavica. (2006) [Pubmed]
  10. Intestinal mast cell responses in idiopathic inflammatory bowel disease. Histamine release from human intestinal mast cells in response to gut epithelial proteins. Fox, C.C., Lichtenstein, L.M., Roche, J.K. Dig. Dis. Sci. (1993) [Pubmed]
  11. System y+ arginine transport and NO production in peripheral blood mononuclear cells in pregnancy and preeclampsia. McCord, N., Ayuk, P., McMahon, M., Boyd, R.C., Sargent, I., Redman, C. Hypertension (2006) [Pubmed]
  12. Requirement of PDZ domains for the stimulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase SGK1. Palmada, M., Poppendieck, S., Embark, H.M., van de Graaf, S.F., Boehmer, C., Bindels, R.J., Lang, F. Cell. Physiol. Biochem. (2005) [Pubmed]
  13. Functional characterisation and genomic analysis of an epithelial calcium channel (ECaC) from pufferfish, Fugu rubripes. Qiu, A., Hogstrand, C. Gene (2004) [Pubmed]
  14. Functional expression of the epithelial Ca(2+) channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex. van de Graaf, S.F., Hoenderop, J.G., Gkika, D., Lamers, D., Prenen, J., Rescher, U., Gerke, V., Staub, O., Nilius, B., Bindels, R.J. EMBO J. (2003) [Pubmed]
  15. Calbindin-D28K dynamically controls TRPV5-mediated Ca2+ transport. Lambers, T.T., Mahieu, F., Oancea, E., Hoofd, L., de Lange, F., Mensenkamp, A.R., Voets, T., Nilius, B., Clapham, D.E., Hoenderop, J.G., Bindels, R.J. EMBO J. (2006) [Pubmed]
  16. Molecular determinants in TRPV5 channel assembly. Chang, Q., Gyftogianni, E., van de Graaf, S.F., Hoefs, S., Weidema, F.A., Bindels, R.J., Hoenderop, J.G. J. Biol. Chem. (2004) [Pubmed]
  17. Diverse Calcium Channel Types are Present in the Human Placental Syncytiotrophoblast Basal Membrane. Bernucci, L., Henríquez, M., Díaz, P., Riquelme, G. Placenta (2006) [Pubmed]
  18. Regulation of the epithelial Ca2+ channels TRPV5 and TRPV6 by 1alpha,25-dihydroxy Vitamin D3 and dietary Ca2+. van de Graaf, S.F., Boullart, I., Hoenderop, J.G., Bindels, R.J. J. Steroid Biochem. Mol. Biol. (2004) [Pubmed]
  19. Immobilization decreases duodenal calcium absorption through a 1,25-dihydroxyvitamin D-dependent pathway. Sato, T., Yamamoto, H., Sawada, N., Nashiki, K., Tsuji, M., Nikawa, T., Arai, H., Morita, K., Taketani, Y., Takeda, E. J. Bone Miner. Metab. (2006) [Pubmed]
  20. Regulation of TRP channels by N-linked glycosylation. Cohen, D.M. Semin. Cell Dev. Biol. (2006) [Pubmed]
  21. The epithelial calcium channels, TRPV5 & TRPV6: from identification towards regulation. den Dekker, E., Hoenderop, J.G., Nilius, B., Bindels, R.J. Cell Calcium (2003) [Pubmed]
  22. Molecular mechanism of active Ca2+ reabsorption in the distal nephron. Hoenderop, J.G., Nilius, B., Bindels, R.J. Annu. Rev. Physiol. (2002) [Pubmed]
  23. Recent advances in renal tubular calcium reabsorption. Mensenkamp, A.R., Hoenderop, J.G., Bindels, R.J. Curr. Opin. Nephrol. Hypertens. (2006) [Pubmed]
  24. Structural conservation of the genes encoding CaT1, CaT2, and related cation channels. Peng, J.B., Brown, E.M., Hediger, M.A. Genomics (2001) [Pubmed]
  25. The immunophilin FKBP52 inhibits the activity of the epithelial Ca2+ channel TRPV5. Gkika, D., Topala, C.N., Hoenderop, J.G., Bindels, R.J. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  26. Ca2+-selective transient receptor potential V channel architecture and function require a specific ankyrin repeat. Erler, I., Hirnet, D., Wissenbach, U., Flockerzi, V., Niemeyer, B.A. J. Biol. Chem. (2004) [Pubmed]
  27. Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. Embark, H.M., Setiawan, I., Poppendieck, S., van de Graaf, S.F., Boehmer, C., Palmada, M., Wieder, T., Gerstberger, R., Cohen, P., Yun, C.C., Bindels, R.J., Lang, F. Cell. Physiol. Biochem. (2004) [Pubmed]
  28. Pharmacological modulation of monovalent cation currents through the epithelial Ca2+ channel ECaC1. Nilius, B., Prenen, J., Vennekens, R., Hoenderop, J.G., Bindels, R.J., Droogmans, G. Br. J. Pharmacol. (2001) [Pubmed]
  29. Molecular cloning, tissue distribution, and chromosomal mapping of the human epithelial Ca2+ channel (ECAC1). Müller, D., Hoenderop, J.G., Meij, I.C., van den Heuvel, L.P., Knoers, N.V., den Hollander, A.I., Eggert, P., García-Nieto, V., Claverie-Martín, F., Bindels, R.J. Genomics (2000) [Pubmed]
  30. Gene structure and chromosomal mapping of human epithelial calcium channel. Müller, D., Hoenderop, J.G., Merkx, G.F., van Os, C.H., Bindels, R.J. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  31. Differential regulation of L-arginine transporters (cationic amino acid transporter-1 and -2) by peroxynitrite in rat mesangial cells. Schwartz, I.F., Chernichovsky, T., Hagin, D., Ingbir, M., Reshef, R., Chernin, G., Levo, Y., Schwartz, D. Nephrol. Dial. Transplant. (2006) [Pubmed]
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