TRPV6 | Transient Receptor Potential channels | IUPHAR/BPS Guide to PHARMACOLOGY

TRPV6

Target id: 512

Nomenclature: TRPV6

Family: Transient Receptor Potential channels

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Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 725 7q33-q34 TRPV6 transient receptor potential cation channel subfamily V member 6 16
Mouse 6 1 727 6 B2 Trpv6 transient receptor potential cation channel, subfamily V, member 6 5
Rat 6 1 727 4q22 Trpv6 transient receptor potential cation channel, subfamily V, member 6 15
Previous and Unofficial Names
CaT1 | CaT-like | ECaC2 | epithelial calcium channel 2 | calcium transport protein 1 | epithelial apical membrane calcium transporter/channel CaT1 | osmosensitive transient receptor potential channel 3 | Otrpc3 | transient receptor potential cation channel
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
TRPV5 7
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Rab11a 20
S100A10/annexin 2 21
NHERF4 22
calmodulin 9
Nipsnap1 18
Functional Characteristics
γ = 58–79 pS for monovalent ions at negative potentials, conducts mono- and di-valents with high selectivity for divalents (PCa/PNa > 130); voltage- and time-dependent inward rectification; inhibited by intracellular Ca2+ promoting fast and slow inactivation; gated by voltage-dependent channel blockade by intracellular Mg2+; slow inactivation due to Ca2+-dependent calmodulin binding; phosphorylation by PKC inhibits Ca2+-calmodulin binding and slow inactivation; upregulated by 1,25-dihydroxyvitamin D3
Ion Selectivity and Conductance
Species:  Mouse
Rank order:  Li+ = Na+ > K+ > Cs+
References:  25
Species:  Rat
Rank order:  Ca2+ > Sr2+ = Ba2+ > Mg2+
References:  30
Ion Selectivity and Conductance Comments
Overall single channel conductance is 42-58 pS [30]. Subject to Mg2+ block. PCa:PNa ratio > 100.
Voltage Dependence Comments
Only block by intracellular Mg2+ displays voltage dependency (V0.5 is approx -50 mV at 1 mM intracellular Mg2+, no extracellular Mg2+, symmetric Na+ [24].
Activators (Human)
constitutively active (with strong buffering of intracellular Ca2+)

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
2-APB Hs Potentiation - - - -
Activator Comments
TRPV6 is constitutively active [15-16]. Extracellular 2-aminoethoxydiphenylborane potentiates TRPV6 [25].
Channel Blockers
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
ruthenium red Mm Antagonist 5.0 pIC50 - -80.0 6
pIC50 5.0 (IC50 9x10-6 M) [6]
Holding voltage: -80.0 mV
Mg2+ Hs - - - - -
La3+ Hs - - - - -
Cd2+ Hs - - - - -
View species-specific channel blocker tables
Immunopharmacology Comments
Expressed on human T cells [12].
Tissue Distribution
Intestines, stomach, placenta, salivary glands, liver, prostate, pancreas, kidney, testes, mammary glands.
Species:  Human
Technique:  In situ hybridisation, Western Blot, Northern Blot, RT-PCR.
References:  5-6,13,16-17,29,31
Intestines, stomach, kidney, lung, spleen, liver, brain, placenta, prostate, pancreas, adrenal glands, skin, bone.
Species:  Mouse
Technique:  Immunocytochemistry, RT-PCR, Northern Blot, Western Blot.
References:  5,26,31
Epididymis
Species:  Mouse
Technique:  RT-PCR, western blot, immunocytochemistry
References:  27-28
Intestines, kidney, brain.
Species:  Rat
Technique:  In situ hybridisation, Northern Blot, RT-PCR.
References:  15
Functional Assays
Patch clamp (whole-cell and single-channel recordings).
Species:  Mouse
Tissue:  HEK cells transfected with the TRPV6 vector.
Response measured:  Ca2+-evoked currents and Mg2+ block.
References:  7-8,11,21,23-25
Two-electrode voltage clamp.
Species:  Rat
Tissue:  Xenopus laevis oocytes injected with TRPV6 cDNA.
Response measured:  Ca2+-evoked currents.
References:  15
Two-electrode voltage clamp.
Species:  Human
Tissue:  Xenopus laevis oocytes injected with TRPV6 cDNA.
Response measured:  Ca2+-evoked currents.
References:  16
Physiological Functions
Ca2+ (re)absorption.
Species:  Mouse
Tissue:  Intestines and kidney.
References:  2,4,10,19,26
Ca2+ (re)absorption.
Species:  Rat
Tissue:  Intestines and kidney.
References:  14-15
Ca2+ (re)absorption.
Species:  Human
Tissue:  Intestines and kidney.
References:  1,31
Ca2+ (re)absorption
Species:  Mouse
Tissue:  Epididymis
References:  27-28
Physiological Consequences of Altering Gene Expression
Decreased intestinal Ca2+ reabsorption.
Species:  Mouse
Tissue:  Intestine
Technique:  Gene knockout, downregulation of TRPV6 expression
References:  2
Alopecia, dermatitis.
Species:  Mouse
Tissue:  Skin and hair follicles.
Technique:  Gene knockout, downregualtion of TRPV6 expression
References:  2
Male infertility
Species:  Mouse
Tissue:  Epididymis
Technique:  Knockout, expression of TRPV6 loss of function pore mutation D541A
References:  27-28
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0004231 abnormal calcium ion homeostasis PMID: 18325990 
Ephb6/Trpv6tm1Mhed|S100gtm1Ebje S100gtm1Ebje/S100gtm1Ebje,Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104528  MGI:1927259  MP:0004231 abnormal calcium ion homeostasis PMID: 18325990 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0001562 abnormal circulating calcium level PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0005401 abnormal fat-soluble vitamin level PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0003953 abnormal hormone level PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0008779 abnormal maternal behavior PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0001670 abnormal mineral absorption PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0000192 abnormal mineral level PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0001384 abnormal pup retrieval PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0002987 abnormal urine osmolality PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0000414 alopecia PMID: 17129178 
Ephb6/Trpv6tm1Mhed|Trpv6+ Ephb6/Trpv6tm1Mhed/Trpv6+
involves: 129S/SvEv
MGI:1927259  MP:0000414 alopecia PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0001262 decreased body weight PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0010121 decreased bone mineral density PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0001935 decreased litter size PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0003620 decreased urine output PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0001194 dermatitis PMID: 17129178 
Ephb6/Trpv6tm1Mhed|Trpv6+ Ephb6/Trpv6tm1Mhed/Trpv6+
involves: 129S/SvEv
MGI:1927259  MP:0001194 dermatitis PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0002904 increased circulating parathyroid hormone level PMID: 18325990 
Ephb6/Trpv6tm1Mhed|S100gtm1Ebje S100gtm1Ebje/S100gtm1Ebje,Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104528  MGI:1927259  MP:0002904 increased circulating parathyroid hormone level PMID: 18325990 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0008489 postnatal slow weight gain PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0001923 reduced female fertility PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0001921 reduced fertility PMID: 17129178 
Ephb6/Trpv6tm1Mhed Ephb6/Trpv6tm1Mhed/Ephb6/Trpv6tm1Mhed
involves: 129S/SvEv
MGI:1927259  MP:0001922 reduced male fertility PMID: 17129178 
Gene Expression and Pathophysiology
Up-regulation.
Tissue or cell type:  Prostate.
Pathophysiology:  Adenocarcinoma.
Species:  Human
Technique: 
References:  17,29
Up-regulation.
Tissue or cell type:  Breast, thyroid, colon, ovary.
Pathophysiology:  Carcinomas
Species:  Human
Technique: 
References:  31
General Comments
In Vivo Detection of Human TRPV6-Rich Tumors with Anti-Cancer Peptides Derived from Soricidin, namely SOR-C13 and SOR-C27, which target tumor sites in mice bearing ovarian or prostate tumors, has been demonstrated [3].

References

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1. Barley NF, Howard A, O'Callaghan D, Legon S, Walters JR. (2001) Epithelial calcium transporter expression in human duodenum. Am. J. Physiol. Gastrointest. Liver Physiol., 280 (2): G285-90. [PMID:11208552]

2. Bianco SD, Peng JB, Takanaga H, Suzuki Y, Crescenzi A, Kos CH, Zhuang L, Freeman MR, Gouveia CH, Wu J, Luo H, Mauro T, Brown EM, Hediger MA. (2007) Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene. J. Bone Miner. Res., 22 (2): 274-85. [PMID:17129178]

3. Bowen CV, DeBay D, Ewart HS, Gallant P, Gormley S, Ilenchuk TT, Iqbal U, Lutes T, Martina M, Mealing G et al.. (2013) In vivo detection of human TRPV6-rich tumors with anti-cancer peptides derived from soricidin. PLoS ONE, 8 (3): e58866. [PMID:23554944]

4. Gkika D, Hsu YJ, van der Kemp AW, Christakos S, Bindels RJ, Hoenderop JG. (2006) Critical role of the epithelial Ca2+ channel TRPV5 in active Ca2+ reabsorption as revealed by TRPV5/calbindin-D28K knockout mice. J. Am. Soc. Nephrol., 17 (11): 3020-7. [PMID:17005931]

5. Hirnet D, Olausson J, Fecher-Trost C, Bödding M, Nastainczyk W, Wissenbach U, Flockerzi V, Freichel M. (2003) The TRPV6 gene, cDNA and protein. Cell Calcium, 33 (5-6): 509-18. [PMID:12765696]

6. Hoenderop JG, Vennekens R, Muller D, Prenen J, Droogmans G, Bindels RJ, Nilius B. (2001) Function and expression of the epithelial Ca(2+) channel family: comparison of mammalian ECaC1 and 2. J. Physiol. (Lond.), 537 (Pt 3): 747-61. [PMID:11744752]

7. Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ. (2003) Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J., 22 (4): 776-85. [PMID:12574114]

8. Lambers TT, Weidema AF, Nilius B, Hoenderop JG, Bindels RJ. (2004) Regulation of the mouse epithelial Ca2(+) channel TRPV6 by the Ca(2+)-sensor calmodulin. J. Biol. Chem., 279 (28): 28855-61. [PMID:15123711]

9. Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C. (2001) Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin. Proc. Natl. Acad. Sci. U.S.A., 98 (6): 3600-5. [PMID:11248124]

10. Nijenhuis T, Hoenderop JG, van der Kemp AW, Bindels RJ. (2003) Localization and regulation of the epithelial Ca2+ channel TRPV6 in the kidney. J. Am. Soc. Nephrol., 14 (11): 2731-40. [PMID:14569082]

11. Nilius B, Prenen J, Hoenderop JG, Vennekens R, Hoefs S, Weidema AF, Droogmans G, Bindels RJ. (2002) Fast and slow inactivation kinetics of the Ca2+ channels ECaC1 and ECaC2 (TRPV5 and TRPV6). Role of the intracellular loop located between transmembrane segments 2 and 3. J. Biol. Chem., 277 (34): 30852-8. [PMID:12077127]

12. Parenti A, De Logu F, Geppetti P, Benemei S. (2016) What is the evidence for the role of TRP channels in inflammatory and immune cells?. Br. J. Pharmacol., 173 (6): 953-69. [PMID:26603538]

13. Peng JB, Brown EM, Hediger MA. (2001) Structural conservation of the genes encoding CaT1, CaT2, and related cation channels. Genomics, 76 (1-3): 99-109. [PMID:11549322]

14. Peng JB, Chen XZ, Berger UV, Vassilev PM, Brown EM, Hediger MA. (2000) A rat kidney-specific calcium transporter in the distal nephron. J. Biol. Chem., 275 (36): 28186-94. [PMID:10875938]

15. Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H, Brown EM, Hediger MA. (1999) Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J. Biol. Chem., 274 (32): 22739-46. [PMID:10428857]

16. Peng JB, Chen XZ, Berger UV, Weremowicz S, Morton CC, Vassilev PM, Brown EM, Hediger MA. (2000) Human calcium transport protein CaT1. Biochem. Biophys. Res. Commun., 278 (2): 326-32. [PMID:11097838]

17. Peng JB, Zhuang L, Berger UV, Adam RM, Williams BJ, Brown EM, Hediger MA, Freeman MR. (2001) CaT1 expression correlates with tumor grade in prostate cancer. Biochem. Biophys. Res. Commun., 282 (3): 729-34. [PMID:11401523]

18. Schoeber JP, Topala CN, Lee KP, Lambers TT, Ricard G, van der Kemp AW, Huynen MA, Hoenderop JG, Bindels RJ. (2008) Identification of Nipsnap1 as a novel auxiliary protein inhibiting TRPV6 activity. Pflugers Arch., 457 (1): 91-101. [PMID:18392847]

19. Van Cromphaut SJ, Dewerchin M, Hoenderop JG, Stockmans I, Van Herck E, Kato S, Bindels RJ, Collen D, Carmeliet P, Bouillon R, Carmeliet G. (2001) Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects. Proc. Natl. Acad. Sci. U.S.A., 98 (23): 13324-9. [PMID:11687634]

20. van de Graaf SF, Chang Q, Mensenkamp AR, Hoenderop JG, Bindels RJ. (2006) Direct interaction with Rab11a targets the epithelial Ca2+ channels TRPV5 and TRPV6 to the plasma membrane. Mol. Cell. Biol., 26 (1): 303-12. [PMID:16354700]

21. van de Graaf SF, Hoenderop JG, Gkika D, Lamers D, Prenen J, Rescher U, Gerke V, Staub O, Nilius B, Bindels RJ. (2003) Functional expression of the epithelial Ca(2+) channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex. EMBO J., 22 (7): 1478-87. [PMID:12660155]

22. van de Graaf SF, Hoenderop JG, van der Kemp AW, Gisler SM, Bindels RJ. (2006) Interaction of the epithelial Ca2+ channels TRPV5 and TRPV6 with the intestine- and kidney-enriched PDZ protein NHERF4. Pflugers Arch., 452 (4): 407-17. [PMID:16565876]

23. Voets T, Janssens A, Droogmans G, Nilius B. (2004) Outer pore architecture of a Ca2+-selective TRP channel. J. Biol. Chem., 279 (15): 15223-30. [PMID:14736889]

24. Voets T, Janssens A, Prenen J, Droogmans G, Nilius B. (2003) Mg2+-dependent gating and strong inward rectification of the cation channel TRPV6. J. Gen. Physiol., 121 (3): 245-60. [PMID:12601087]

25. Voets T, Prenen J, Fleig A, Vennekens R, Watanabe H, Hoenderop JG, Bindels RJ, Droogmans G, Penner R, Nilius B. (2001) CaT1 and the calcium release-activated calcium channel manifest distinct pore properties. J. Biol. Chem., 276 (51): 47767-70. [PMID:11687570]

26. Weber K, Erben RG, Rump A, Adamski J. (2001) Gene structure and regulation of the murine epithelial calcium channels ECaC1 and 2. Biochem. Biophys. Res. Commun., 289 (5): 1287-94. [PMID:11741335]

27. Weissgerber P, Kriebs U, Tsvilovskyy V, Olausson J, Kretz O, Stoerger C, Mannebach S, Wissenbach U, Vennekens R, Middendorff R et al.. (2012) Excision of Trpv6 gene leads to severe defects in epididymal Ca2+ absorption and male fertility much like single D541A pore mutation. J. Biol. Chem., 287 (22): 17930-41. [PMID:22427671]

28. Weissgerber P, Kriebs U, Tsvilovskyy V, Olausson J, Kretz O, Stoerger C, Vennekens R, Wissenbach U, Middendorff R, Flockerzi V et al.. (2011) Male fertility depends on Ca²+ absorption by TRPV6 in epididymal epithelia. Sci Signal, 4 (171): ra27. [PMID:21540454]

29. Wissenbach U, Niemeyer BA, Fixemer T, Schneidewind A, Trost C, Cavalie A, Reus K, Meese E, Bonkhoff H, Flockerzi V. (2001) Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer. J. Biol. Chem., 276 (22): 19461-8. [PMID:11278579]

30. Yue L, Peng JB, Hediger MA, Clapham DE. (2001) CaT1 manifests the pore properties of the calcium-release-activated calcium channel. Nature, 410 (6829): 705-9. [PMID:11287959]

31. Zhuang L, Peng JB, Tou L, Takanaga H, Adam RM, Hediger MA, Freeman MR. (2002) Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab. Invest., 82 (12): 1755-64. [PMID:12480925]

Contributors

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How to cite this page

Dan Tong, David E. Clapham.
Transient Receptor Potential channels: TRPV6. Last modified on 23/05/2017. Accessed on 15/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=512.