Alternative titles; symbols
HGNC Approved Gene Symbol: TRPC6
Cytogenetic location: 11q22.1 Genomic coordinates (GRCh38): 11:101,451,564-101,584,007 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.1 | Glomerulosclerosis, focal segmental, 2 | 603965 | Autosomal dominant | 3 |
TRPCs, mammalian homologs of the Drosophila transient receptor potential (trp) protein, are ion channels that are thought to mediate capacitative calcium entry into the cell. Using a PCR-based strategy, Hofmann et al. (1999) isolated cDNAs encoding TRPC6, a novel member of the TRPC family. The predicted 931-amino acid protein shares 93% identity with mouse Trpc6. Northern blot analysis revealed that TRPC6 is expressed primarily in placenta, lung, spleen, ovary, and small intestine.
Hofmann et al. (1999) found that TRPC6 is a nonselective cation channel that is activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C. Although TRPC3 (602345), the closest structural relative of TRPC6, is activated in the same manner, human TRPC1 and mouse Trpc4 (603651) and Trpc5 (300334) were unresponsive to DAG. The authors suggested that TRPC3 and TRPC6 represent the first members of a new functional family of second-messenger-operated cation channels that are activated by DAG.
Pulmonary vascular medial hypertrophy caused by excessive proliferation of pulmonary artery smooth muscle cells (PASMC) is a major cause for the elevated pulmonary vascular resistance in patients with idiopathic, or primary, pulmonary arterial hypertension (178600). Increased Ca(2+) influx is an important stimulus for PASMC proliferation. Transient receptor potential (TRP) channel genes encode Ca(2+) channels that are responsible for Ca(2+) entry during cell proliferation. Yu et al. (2004) found that normal human PASMC express multiple canonic TRCP isoforms; TRPC6 was highly expressed and TRPC3 was minimally expressed. Protein expression of TRPC6 in normal PASMC closely correlated with the expression of Ki67, suggesting that TRPC6 expression is involved in the transition of PASMC from quiescent phase to mitosis. In lung tissues and PASMC from patients with idiopathic pulmonary arterial hypertension, mRNA and protein expression of TRPC3 and TRPC6 were much higher than in those from normotensive or secondary pulmonary hypertension patients. Inhibition of TRPC6 expression with TRPC6 small interfering RNA (siRNA) markedly attenuated proliferation of PASMC in hypertensive patients. These results demonstrated that expression of TRPC channels correlates with the progression of the cell cycle in PASMC. TRPC channel overexpression may be partially responsible for the increased PASMC proliferation and pulmonary vascular medial hypertrophy in idiopathic pulmonary hypertension.
Reiser et al. (2005) examined the expression of TRPC6 in the kidney. Confocal microscopy of adult rat kidney sections showed broad expression of TRPC6 throughout the kidney in tubules and glomeruli. Immunofluorescence studies showed that most TRPC6 expression is confined to podocytes. TRPC6 was also expressed in glomerular endothelial cells.
Li et al. (2005) reported that in cultured cerebellar granule cells, TRPC channels contribute to the BDNF-induced elevation of calcium at the growth cone and are required for BDNF-induced chemoattractive turning. They observed that several members of the TRPC family are highly expressed in these neurons, and both calcium elevation and growth cone turning induced by BDNF were abolished by pharmacologic inhibition of TRPC channels, overexpression of a dominant-negative form of TRPC3 (602345) or TRPC6, or downregulation of TRPC3 expression via short interfering RNA (siRNA). Thus, TRPC channel activity is essential for nerve-growth-cone guidance by BDNF.
Using RT-PCR, Kuwahara et al. (2006) found that Trpc6 was upregulated in hypertrophic hearts of both calcineurin (see 114105) transgenic mice and wildtype mice subjected to pressure overload. RT-PCR showed increased TRPC6 expression in 3 human hearts with dilated cardiomyopathy compared with normal controls. Kuwahara et al. (2006) identified 2 NFAT (see 602698) consensus sites within the promoter regions of rat, mouse, and human TRPC6 that could confer responsiveness to cardiac stress. 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 (MYH7; 160760), a marker for pathologic hypertrophy.
Kwon et al. (2007) fused residues 728 to 981 of the C terminus of human TRPC6 to maltose-binding protein and showed that C-terminal TRPC6 mediated binding between the fusion protein and phosphoinositides, with highest affinity for phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 binding disrupted the association between calmodulin and C-terminal TRPC6. Mutations in the PtdIns(3,4,5)P3-binding site that increased or decreased the affinity between PtdIns(3,4,5)P3 and C-terminal TRPC6 enhanced or reduced the TRPC6 currents, respectively.
By FISH, D'Esposito et al. (1998) mapped the TRPC6 gene to chromosome 11q21-q22.
In a family with autosomal dominant focal segmental glomerulosclerosis that mapped to 11q (FSGS2; 603965), Winn et al. (2005) identified a point mutation in the TRPC6 gene. Reiser et al. (2005) identified 5 families with autosomal dominant glomerulosclerosis in which the disease segregated with mutations in the TRPC6 gene on 11q. Two of the TRPC6 mutants had increased current amplitudes. These data showed that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.
Freichel et al. (2004) reviewed Trpc-deficient mouse models. They stated that studies of Trpc6 -/- mice showed that Trpc6 has a role in regulation of smooth muscle tone in blood vessels and lung.
In a large family with hereditary focal segmental glomerulosclerosis (FSGS2; 603965) identified by Winn et al. (1999), Winn et al. (2005) detected a 335C-A transversion in exon 2 of the TRPC6 gene that resulted in a pro112-to-gln (P112Q) amino acid substitution within the first ankyrin repeat of the TRPC6 protein. The P112Q mutation occurred in a highly conserved region of the protein, enhanced TRPC6-mediated calcium signals in response to antagonists such as angiotensin II (see 106150), and appeared to alter the intracellular distribution of TRPC6 protein.
Reiser et al. (2005) identified an asn143-to-ser (N143S) mutation in the TRPC6 gene in members of an African American family with focal segmental glomerulosclerosis (FSGS2; 603965). Five of 36 members had end-stage renal disease (ESRD). Presentation of the disease varied from 27 to 39 years.
In a Colombian family with focal segmental glomerulosclerosis (FSGS2; 603965) presenting at ages 17 to 52 years and in which 3 of 12 members had ESRD, Reiser et al. (2005) found a ser270-to-thr (S270T) mutation in the TRPC6 gene segregating with the phenotype.
In a Polish family with focal segmental glomerulosclerosis (FSGS2; 603965) that presented between 27 and 57 years of age and in which 9 of 53 family members had ESRD, Reiser et al. (2005) found a lys874-to-stop (K874X) mutation in the TRPC6 gene in affected members.
In a Mexican family with focal segmental glomerulosclerosis (FSGS2; 603965) that presented between the ages of 18 and 46 and in which 6 of 25 family members had ESRD, Reiser et al. (2005) found an arg895-to-cys (R895C) mutation in the TRPC6 gene in affected individuals.
In a family of Irish and German ancestry with focal segmental glomerulosclerosis (FSGS2; 603965) that presented between 24 and 35 years of age and in which 2 of 12 family members had ESRD, Reiser et al. (2005) found a glu897-to-lys (E897K) mutation in the TRPC6 gene in affected members.
D'Esposito, M., Strazzullo, M., Cuccurese, M., Spalluto, C., Rocchi, M., D'Urso, M., Ciccodicola, A. Identification and assignment of the human transient receptor potential channel 6 gene TRPC6 to chromosome 11q21-q22. Cytogenet. Cell Genet. 83: 46-47, 1998. [PubMed: 9925922] [Full Text: https://doi.org/10.1159/000015165]
Freichel, M., Vennekens, R., Olausson, J., Hoffmann, M., Muller, C., Stolz, S., Scheunemann, J., Weissgerber, P., Flockerzi, V. Functional role of TRPC proteins in vivo: lessons from TRPC-deficient mouse models. Biochem. Biophys. Res. Commun. 322: 1352-1358, 2004. [PubMed: 15336983] [Full Text: https://doi.org/10.1016/j.bbrc.2004.08.041]
Hofmann, T., Obukhov, A. G., Schaefer, M., Harteneck, C., Gudermann, T., Schultz, G. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397: 259-263, 1999. [PubMed: 9930701] [Full Text: https://doi.org/10.1038/16711]
Kuwahara, K., Wang, Y., McAnally, J., Richardson, J. A., Bassel-Duby, R., Hill, J. A., Olson, E. N. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J. Clin. Invest. 116: 3114-3126, 2006. [PubMed: 17099778] [Full Text: https://doi.org/10.1172/JCI27702]
Kwon, Y., Hofmann, T., Montell, C. Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6. Molec. Cell 25: 491-503, 2007. [PubMed: 17317623] [Full Text: https://doi.org/10.1016/j.molcel.2007.01.021]
Li, Y., Jia, J.-C., Cui, K., Li, N., Zheng, Z.-Y., Wang, Y., Yuan, X. Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor. Nature 434: 894-898, 2005. [PubMed: 15758952] [Full Text: https://doi.org/10.1038/nature03477]
Reiser, J., Polu, K. R., Moller, 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. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nature Genet. 37: 739-744, 2005. [PubMed: 15924139] [Full Text: https://doi.org/10.1038/ng1592]
Winn, M. P., Conlon, P. J., Lynn, K. L., Farrington, M. K., Creazzo, T., Hawkins, A. F., Daskalakis, N., Kwan, S. Y., Ebersviller, S., Burchette, J. L., Pericak-Vance, M. A., Howell, D. N., Vance, J. M., Rosenberg, P. B. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308: 1801-1804, 2005. [PubMed: 15879175] [Full Text: https://doi.org/10.1126/science.1106215]
Winn, M. P., Conlon, P. J., Lynn, K. L., Howell, D. N., Gross, D. A., Rogala, A. R., Smith, A. H., Graham, F. L., Bembe, M., Quarles, L. D., Pericak-Vance, M. A., Vance, J. M. Clinical and genetic heterogeneity in familial focal segmental glomerulosclerosis. Kidney Int. 55: 1241-1246, 1999. [PubMed: 10200986] [Full Text: https://doi.org/10.1046/j.1523-1755.1999.00384.x]
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.-J. Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc. Nat. Acad. Sci. 101: 13861-13866, 2004. [PubMed: 15358862] [Full Text: https://doi.org/10.1073/pnas.0405908101]