Nomenclature: TRPC6

Family: Transient Receptor Potential channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 931 11q21-q22 TRPC6 transient receptor potential cation channel, subfamily C, member 6 12
Mouse 6 1 930 9 A1 Trpc6 transient receptor potential cation channel, subfamily C, member 6 3
Rat 6 1 930 8q11 Trpc6 transient receptor potential cation channel, subfamily C, member 6 22
Previous and Unofficial Names
Names References
TRP6 14
Trrp6
short transient receptor potential channel 6
transient receptor potential cation channel, subfamily C, member 6
transient receptor protein 6
mtrp6
AV025995
Database Links
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
TRPC7 7
TRPC3 7
TRPC4 28
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
FKBP12 29
calmodulin 2,4,9
SNF8 5
Functional Characteristics
γ = 28-37 pS; conducts mono and divalent cations with a preference for divalents (PCa/PNa = 4.5–5.0); monovalent cation current suppressed by extracellular Ca2+ and Mg2+, dual rectification (inward and outward), or inward rectification
Ion Selectivity and Conductance
Species:  Human
Rank order:  Ca2+ > Cs+ > Na+
References:  12
Ion Selectivity and Conductance Comments
Slope conductance of 35pS in symmetrical 120mM Cs+ [12].
Other chemical activators (Human)
Diacylglycerols
Physical activators (Human)
Membrane stretch (likely indirect)
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
SLG Hs Agonist - - 1x10-4 -60.0 12
Conc range: 1x10-4 M [12]
Holding voltage: -60.0 mV
OAG Hs Agonist - - 1x10-4 -60.0 12
Conc range: 1x10-4 M [12]
Holding voltage: -60.0 mV
SAG Hs Agonist - - 1x10-5 -60.0 12
Conc range: 1x10-5 M [12]
Holding voltage: -60.0 mV
hyperforin Hs - - - - - 17
[17]
2,4 diahexanxoylphloroglucinol Hs - - - - - 16
[16]
flufenamate Hs - - - - -
lysophosphatidylcholine Hs - - - - -
20-HETE Hs - - - - -
arachidonic acid Hs - - - - -
Activator Comments
The naturally occurring plant compound hyperforin has been identified as a selective activator of the mouse TRPC6 channel [10].
Channel Blockers
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
Gd3+ Mm Antagonist 5.7 pIC50 - -60.0 14
pIC50 5.7 (IC50 1.9x10-6 M) [14]
Holding voltage: -60.0 mV
La3+ Mm Antagonist 5.4 pIC50 - -60.0 14
pIC50 5.4 [14]
Holding voltage: -60.0 mV
SKF96365 Mm Antagonist 5.4 pIC50 - -60.0 14
pIC50 5.4 (IC50 4.2x10-6 M) [14]
Holding voltage: -60.0 mV
La3+ Hs - ~5.22 pIC50 - -
pIC50 ~5.22 (IC50 ~6x10-6 M)
amiloride Mm Antagonist 3.9 pIC50 - -60.0 14
pIC50 3.9 (IC50 1.29x10-4 M) [14]
Holding voltage: -60.0 mV
Cd2+ Mm Antagonist 3.6 pIC50 - -60.0 14
pIC50 3.6 (IC50 2.53x10-4 M) [14]
Holding voltage: -60.0 mV
Extracellular H+ Hs - - - - -
GsMTx-4 Hs - - - - -
KB-R7943 Hs - - - - -
ACAA Hs - - - - -
2-APB Hs - - - - -
ML9 Hs - - - - -
View species-specific channel blocker tables
Tissue Distribution
Heart, lung, kidney, muscle, intestine, stomach, pancreas, prostate, bone, brain.
Species:  Human
Technique:  RT-PCR
References:  20
Testis, lung spleen, epididymis, ovary, brain , retina, iris, heart, kidney and liver.
Species:  Mouse
Technique:  RT-PCR, western blot and immunohistochemistry.
References:  13,15,23
Brain, kidney, heart, lung, adrenal gland.
Species:  Rat
Technique:  RT-PCR
References:  18
Functional Assays
Cation influx in response to DAG generated by receptor-mediated activation of PLC-β and PLC-γ.
Species:  Human
Tissue:  CHO-K1 cells.
Response measured:  Cation influx, using calcium imaging and patch clamp.
References:  12
Physiological Functions
TRPC6 is essential for proper regulation of podocyte structure and function.
Species:  Human
Tissue:  Kidney.
References:  11,19,25
Physiological Consequences of Altering Gene Expression
The trpc6 knockout mouse has increased vascular smooth muscle contractility.
Species:  Mouse
Tissue:  Vascular smooth muscle
Technique: 
References:  8
Trpc6 null mice show a reduced exploration in the square open field and the elevated star maze tests.
Species:  Mouse
Tissue:  Brain
Technique: 
References:  1
Transgenic mouse expressing dominant-negative Trpc6 shows attenuated cardiac hypertrophic response following pressure-overload stimulation.
Species:  Mouse
Tissue:  Heart
Technique: 
References:  26
In mice, ablating the expression of both Trpc6 and Trpc7 eliminates intrinsic light response of the M1 subtype of melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (M1-ipRGCs).
Species:  Mouse
Tissue:  Retina, iris
Technique: 
References:  27
Loss of Trpc6 reduces allergic airway response and indicates that activation of Trpc6 channels is essential for lung ischemia-reperfusion induced oedema in mice.
Species:  Mouse
Tissue:  Lung
Technique: 
References:  21,24
Trpc6 null mice show impaired dermal and cardiac wound healing after injury.
Species:  Mouse
Tissue:  Heart
Technique: 
References:  6
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Trpc6tm1Lbi Trpc6tm1Lbi/Trpc6tm1Lbi
involves: 129S/SvEv * C57BL/6J
MGI:109523  MP:0005595 abnormal vascular smooth muscle physiology PMID: 16055711 
Trpc6tm1Lbi Trpc6tm1Lbi/Trpc6tm1Lbi
involves: 129S/SvEv * C57BL/6J
MGI:109523  MP:0000250 abnormal vasoconstriction PMID: 16055711 
Trpc6tm1Lbi Trpc6tm1Lbi/Trpc6tm1Lbi
involves: 129S/SvEv * C57BL/6J
MGI:109523  MP:0002842 increased systemic arterial blood pressure PMID: 16055711 
Trpc6tm1Lbi Trpc6tm1Lbi/Trpc6tm1Lbi
involves: 129S/SvEv * C57BL/6J
MGI:109523  MP:0003025 increased vasoconstriction PMID: 16055711 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Focal segmental glomerulosis (FSGS)
OMIM:  603965
Orphanet:  93213
References:  19,25
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human R895C 19,25
Missense Human S270T 19,25
Missense Human N143S 19,25
Missense Human M132T 11
Truncation Human K874X 19,25

REFERENCES

1. 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): 245-50. [PMID:21059368]

2. Boulay G. (2002) Ca(2+)-calmodulin regulates receptor-operated Ca(2+) entry activity of TRPC6 in HEK-293 cells. Cell Calcium32 (4): 201-7. [PMID:12379180]

3. 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): 29672-80. [PMID:9368034]

4. Boulay ME, Boulet LP. (2002) Lower airway inflammatory responses to repeated very-low-dose allergen challenge in allergic rhinitis and asthma. Clin. Exp. Allergy32 (10): 1441-7. [PMID:12372123]

5. Carrasquillo R, Tian D, Krishna S, Pollak MR, Greka A, Schlöndorff J. (2012) SNF8, a member of the ESCRT-II complex, interacts with TRPC6 and enhances its channel activity. BMC Cell Biol.13: 33. [PMID:23171048]

6. Davis J, Burr AR, Davis GF, Birnbaumer L, Molkentin JD. (2012) A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev. Cell23 (4): 705-15. [PMID:23022034]

7. Dietrich A, Kalwa H, Rost BR, Gudermann T. (2005) The diacylgylcerol-sensitive TRPC3/6/7 subfamily of cation channels: functional characterization and physiological relevance. Pflugers Arch.451 (1): 72-80. [PMID:15971081]

8. Dietrich A, Mederos Y Schnitzler M, 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): 6980-9. [PMID:16055711]

9. Friedlova E, Grycova L, Holakovska B, Silhan J, Janouskova H, Sulc M, Obsilova V, Obsil T, Teisinger J. (2010) The interactions of the C-terminal region of the TRPC6 channel with calmodulin. Neurochem. Int.56 (2): 363-6. [PMID:19932145]

10. Harteneck C, Gollasch M. (2011) Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels. Curr Pharm Biotechnol12 (1): 35-41. [PMID:20932261]

11. Heeringa SF, Möller CC, Du J, Yue L, Hinkes B, Chernin G, Vlangos CN, Hoyer PF, Reiser J, Hildebrandt F. (2009) A novel TRPC6 mutation that causes childhood FSGS. PLoS ONE4 (11): e7771. [PMID:19936226]

12. Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G. (1999) Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature397 (6716): 259-63. [PMID:9930701]

13. Inada H, Iida T, Tominaga M. (2006) Different expression patterns of TRP genes in murine B and T lymphocytes. Biochem. Biophys. Res. Commun.350 (3): 762-7. [PMID:17027915]

14. 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): 325-32. [PMID:11179201]

15. Jang Y, Lee Y, Kim SM, Yang YD, Jung J, Oh U. (2012) Quantitative analysis of TRP channel genes in mouse organs. Arch. Pharm. Res.35 (10): 1823-30. [PMID:23139135]

16. Leuner K, Heiser JH, Derksen S, Mladenov MI, Fehske CJ, Schubert R, Gollasch M, Schneider G, Harteneck C, Chatterjee SS et al.. (2010) Simple 2,4-diacylphloroglucinols as classic transient receptor potential-6 activators--identification of a novel pharmacophore. Mol. Pharmacol.77 (3): 368-77. [PMID:20008516]

17. Leuner K, Kazanski V, Müller M, Essin K, Henke B, Gollasch M, Harteneck C, Müller WE. (2007) Hyperforin--a key constituent of St. John's wort specifically activates TRPC6 channels. FASEB J.21 (14): 4101-11. [PMID:17666455]

18. Mizuno N, Kitayama S, Saishin Y, Shimada S, Morita K, Mitsuhata C, Kurihara H, Dohi T. (1999) Molecular cloning and characterization of rat trp homologues from brain. Brain Res. Mol. Brain Res.64 (1): 41-51. [PMID:9889314]

19. 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): 739-44. [PMID:15924139]

20. Riccio A, Medhurst AD, Mattei C, Kelsell RE, Calver AR, Randall AD, Benham CD, Pangalos MN. (2002) mRNA distribution analysis of human TRPC family in CNS and peripheral tissues. Brain Res. Mol. Brain Res.109 (1-2): 95-104. [PMID:12531519]

21. 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. Allergy38 (9): 1548-58. [PMID:18631347]

22. 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): 39786-94. [PMID:16204251]

23. Takumida M, Anniko M. (2009) Expression of canonical transient receptor potential channel (TRPC) 1-7 in the mouse inner ear. Acta Otolaryngol.129 (12): 1351-8. [PMID:19922081]

24. Weissmann N, Sydykov A, Kalwa H, Storch U, Fuchs B, Mederos y Schnitzler M, Brandes RP, Grimminger F, Meissner M, Freichel M et al.. (2012) Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice. Nat Commun3: 649. [PMID:22337127]

25. 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. Science308 (5729): 1801-4. [PMID:15879175]

26. Wu X, Eder P, Chang B, Molkentin JD. (2010) TRPC channels are necessary mediators of pathologic cardiac hypertrophy. Proc. Natl. Acad. Sci. U.S.A.107 (15): 7000-5. [PMID:20351294]

27. Xue T, Do MT, Riccio A, Jiang Z, Hsieh J, Wang HC, Merbs SL, Welsbie DS, Yoshioka T, Weissgerber P et al.. (2011) Melanopsin signalling in mammalian iris and retina. Nature479 (7371): 67-73. [PMID:22051675]

28. Yuan JP, Zeng W, Dorwart MR, Choi YJ, Worley PF, Muallem S. (2009) SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat. Cell Biol.11 (3): 337-43. [PMID:19182790]

29. Zagranichnaya TK, Wu X, Villereal ML. (2005) Endogenous TRPC1, TRPC3, and TRPC7 proteins combine to form native store-operated channels in HEK-293 cells. J. Biol. Chem.280 (33): 29559-69. [PMID:15972814]

To cite this database page, please use the following:

Antonio Riccio, David E. Clapham.
Transient Receptor Potential channels: TRPC6. Last modified on 13/02/2014. Accessed on 30/09/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=491.

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