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HGNC Approved Gene Symbol: TRPC4
Cytogenetic location: 13q13.3 Genomic coordinates (GRCh38) : 13:37,632,063-37,869,772 (from NCBI)
Mammalian genes related to the Drosophila transient receptor potential (trp) gene are thought to encode proteins that form capacitative calcium entry (CCE) channels. Zhu et al. (1996) identified cDNAs encoding 2 novel human trp-related genes, TRPC3 (602345) and TRPC4, and reported the existence of 6 trp-related genes in the mouse genome.
McKay et al. (2000) amplified TRPC4 by PCR from a human embryonic kidney cell line using degenerate oligonucleotides based on the bovine TRPC4 sequence. The full-length cDNA, subsequently cloned from a human kidney library, encodes a deduced 977-amino acid protein with a calculated molecular mass of 112 kD. TRPC4 contains 6 transmembrane regions, a pore region, a caveolin-binding domain and a PDZ domain binding region at the C terminus. TRPC4 shares 97.1%, 97.1%, and 91.3% sequence identity with the bovine, mouse, and rat homologous proteins, respectively. Northern blot analysis identified 3 TRPC4 transcripts of 4.0 kb, 4.3 kb, and 7.4 kb, with expression of one or more of them in adult heart, pancreas, placenta, brain, and kidney. No banding was seen in lung, liver, or skeletal muscle. Using Southern blot analysis of PCR products, additional positive tissues were identified, including adrenals, uterus, prostate, lymphocytes, and fetal brain. Immunofluorescence studies demonstrated a pattern of localization similar to that for TRPC3, with punctate staining at the plasma membrane, near the Golgi apparatus, and in the cytoplasm.
Schaefer et al. (2002) identified a splice variant of TRPC4 in total RNA of pooled human testis. They named the full-length protein TRPC4-alpha, and the shorter variant, lacking an 84-amino acid domain in the cytosolic C terminus, TRPC4-beta. Schaefer et al. (2002) demonstrated that the alpha and beta isoforms integrated equally well into the plasma membrane of transfected cells.
Using patch-clamp and whole-cell recordings of human embryonic kidney cells transiently transfected with TRPC4, Schaefer et al. (2002) found that, when transfected individually, both TRPC4-alpha and TRPC4-beta formed cation channels with activation independent of calcium stores. Phospholipase C-coupled receptor activation led to a stronger response from the TRPC4-beta, and cotransfection resulted in heteromultimers with reduced response to receptor stimulation due to a C-terminal autoinhibitory domain in TRPC4-alpha.
McKay et al. (2000) mapped the TRPC4 gene to chromosome 13q13.1-q13.2 by fluorescence in situ hybridization.
Freichel et al. (2004) reviewed Trpc-deficient mouse models. They stated that studies of Trpc4 -/- mice showed that Trpc4 has an essential role in endothelial-dependent regulation of vascular tone, endothelial permeability, and neurotransmitter release from thalamic interneurons.
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]
McKay, R. R., Szymeczek-Seay, C. L., Lievremont, J. P., Bird, G. S. J., Zitt, C., Jungling, E., Luckhoff, A., Putney, J. W., Jr. Cloning and expression of the human transient receptor potential 4 (TRP4) gene: localization and functional expression of human TRP4 and TRP3. Biochem. J. 351: 735-746, 2000. [PubMed: 11042129]
Schaefer, M., Plant, T. D., Stresow, N., Albrecht, N., Schultz, G. Functional differences between TRPC4 splice variants. J. Biol. Chem. 277: 3752-3759, 2002. [PubMed: 11713258] [Full Text: https://doi.org/10.1074/jbc.M109850200]
Zhu, X., Jiang, M., Peyton, M., Boulay, G., Hurst, R., Stefani, E., Birnbaumer, L. Trp, a novel mammalian gene family essential for agonist-activated capacitative Ca(2+) entry. Cell 85: 661-671, 1996. [PubMed: 8646775] [Full Text: https://doi.org/10.1016/s0092-8674(00)81233-7]