Disease relevance of TRPC1

• Capacitative Ca2+ entries and mRNA expression for TRPC1 and TRPC5 channels in human epidermoid carcinoma A431 cells [1].
• There is good evidence to implicate TRPC1 in neointimal hyperplasia after vascular injury via store-depletion-operated Ca2+ entry [2].
• This study examined the role of TRPC1 in human neuroblastoma (SH-SY5Y) cells [3].
• We conclude that, in prostate cancer epithelial cells, alpha1-ARs and m1-AChRs are functionally coupled to Ca2+-permeable DAG-gated cationic channels, for which TRPC1 and TRPC3 are the most likely candidates [4].
• TRPC1 expression was reduced in a stable A7r5 cell line expressing a small interfering RNA (siRNA) or by infection of A7r5 cells with an adenovirus expressing a TRPC1 antisense nucleotide sequence [5].

High impact information on TRPC1

• Expression in COS cells of two full-length cDNAs encoding human trp homologs, Htrp1 and Htrp3, increased CCE [6].
• Drosophila transient receptor potential (TRP) proteins and some mammalian homologues (TRPC proteins) are thought to mediate capacitative Ca2+ entry [7].
• Calmodulin regulates Ca(2+)-dependent feedback inhibition of store-operated Ca(2+) influx by interaction with a site in the C terminus of TrpC1 [8].
• Notably, the cytosolic carboxyl terminus of STIM1 is sufficient to activate SOC, I(crac) and TRPC1 channels even when native STIM1 is depleted by small interfering RNA [9].
• Deletion of either region in the constitutively active STIM1(D76A) yields dominant-negative mutants that block native SOC channels, expressed TRPC1 in HEK293 cells and I(crac) in Jurkat cells [9].

Chemical compound and disease context of TRPC1

• TRPC1-mediated inhibition of 1-methyl-4-phenylpyridinium ion neurotoxicity in human SH-SY5Y neuroblastoma cells [3].
• Taken together, these findings suggest that the reduction in cell surface TRPC1 protein expression in response to salsolinol may be a contributory factor in cellular toxicity of the dopaminergic neurons [10] .

Biological context of TRPC1

• To address the contribution of NF-kappaB in the mechanism of TRPC1 expression, we determined the effects of TNF-alpha on expression of the reporter luciferase after transfection of hTRPC1 promoter-luciferase (hTRPC1-Pro-Luc) construct in the human dermal microvascular endothelial cell line [11].
• Treatment with NEMO-binding domain peptide, which prevents NF-kappaB activation by selectively inhibiting IKKgamma interaction with IKK complex, also blocked the TNF-alpha-induced TRPC1 expression [11].
• The association of TRPC1 with PLCgamma1 and IP3R decreased in keratinocytes with higher intracellular Ca2+, coinciding with a downregulation in SOC activity [12].
• Biotinylation revealed the presence of TRPC1! in the plasma membrane of resting platelets [13].
• Immunofluorescent staining and/or Western blotting of arteries and isolated cells showed upregulation of TRPC1 and TRPC6 proteins during organ culture [14].

Anatomical context of TRPC1

• Tumor necrosis factor-alpha induces nuclear factor-kappaB-dependent TRPC1 expression in endothelial cells [11].
• Here we show that HASM and human bronchial epithelial cells both express TRPC1, -4, and -6, with HASM also expressing TRPC3 at the mRNA level [15].
• TRPC3 and TRPC6 were also detected in primary podocyte cultures, whereas TRPC1 was exclusively expressed in mesangial cell cultures [16].
• Additionally for TRPC1, a larger species, and for TRPC2, a smaller species was detected in all three cell lines with sequencing revealing the fragments to contain TRPC sequence, suggesting that they were either products of alternative splicing events or from closely related genes [17].
• Inhibition of TRPC1 expression or block by TRPC1-specific antibody leads to attenuation of the plasma membrane calcium influx that occurs in response to depletion of calcium levels in sarcoplasmic or endoplasmic reticulum [18].

Associations of TRPC1 with chemical compounds

• TRPC1/TRPC5 heteromers were activated by G(q)-coupled receptors but not by depletion of intracellular Ca(2+) stores [19].
• The suppression of either TRPC3 or TRPC7, but not TRPC1, induced a high Ba(2+) leak flux that was inhibited by 2-APB and SKF96365, suggesting that the influx is via leaky store-operated channels [20].
• These results suggest that TRPC1, -C3, and -C6 may play a functional role in PLC-dependent signaling in specific regions of the nephron [16].
• Thus lowering the levels of cellular calcium with the chelators EGTA and BAPTA AM results in a downregulation of TRPC1-TRPC4 gene and protein expression [21].
• It encodes a putative variant of the C3-type TRPC (transient receptor potential channel) that differs from the previously cloned murine TRPC3 cDNA in that it has a 5' extension stemming from inclusion of an additional exon (exon 0) [22].
• Overexpression of TRPC1 or SERCA2-siRNA in HaCaT cells demonstrated resistance to thapsigargin-induced apoptosis [23].
• TRPC isolation from protein complexes using ProCISA revealed that hTRPC1, 4 and 5 were not tyrosine phosphorylated at rest or after Thr stimulation [24].
• Electrotransjection of cells with anti-Orai1 antibody, directed toward the C-terminal region that mediates the interaction with STIM1, and stabilization of an actin cortical barrier with jasplakinolide prevented the interaction between STIM1 and hTRPC1 [25].

Physical interactions of TRPC1

• Conversely, TRPC1 co-immunoprecipitated with TRPC3 [26].
• Using a GST pull-down and co-immunoprecipitation assay, we showed that MxA interacted with TRPC1, -3, -4, -5, -6, and -7 [27].
• The purpose of the present study was to determine if mammalian FKBP12 or FKBP52 interact with TRPC channel proteins [28].
• Full-length Cav1 bound to both the N and C termini of TRPC1 [29].
• We found that the synaptosome-associated protein (SNAP-25) and the vesicle-associated membrane proteins (VAMP) coimmunoprecipitate with hTRPC1 in platelets [30].

Regulatory relationships of TRPC1

• Expression of antisense TRPC1 decreased (i) Tg- and OAG-stimulated currents and Ca2+ entry and (ii) the level of endogenous TRPC1 but not TRPC4 [26].
• Thus, TNF-alpha induces TRPC1 expression through an NF-kappaB-dependent pathway in endothelial cells, which can trigger augmented Ca2+ entry following Ca2+ store depletion [11].
• Anti-TRPC1 antibody inhibited the VEGF-induced Ca2+ entry and the increased endothelial permeability [31].
• TRPC5 is expressed in smooth muscle cells of human vein along with TRPC1, which forms a complex with TRPC5 [32].
• Caveolin-1 contributes to assembly of store-operated Ca2+ influx channels by regulating plasma membrane localization of TRPC1 [29].

Other interactions of TRPC1

• The C-terminal domain is sufficient but not necessary for the PKD2-TRPC1 association [33].
• However, distinct residues within this region mediate specific interactions with TRPC1 or PKD1 [33].
• Furthermore, coimmunoprecipitation experiments and immunofluorescent double staining displayed that TRPC1 had physical interaction with TRPC4 and 6, while no interactions were detected among other isoforms of TRPCs [34].
• After dilatation, TRPC1 and TRPC6 mRNA were progressively increased compared with undilated control segments [14].
• This study investigated gestational regulation of transient receptor potential canonical (TrpC) proteins, putative calcium entry channels in human myometrium, and the potential modulation of TrpC expression by IL-1 beta, a cytokine implicated in labor [35].

Analytical, diagnostic and therapeutic context of TRPC1

• Western blotting showed that TRPC1, 3, 4, and 6 were expressed in cultured HMCs [34].
• The expression of TRPC1, 3, 4, and 6 was also observed in rat and human glomeruli using fluorescent immunohistochemistry [34].
• Consistently, immunofluorescent confocal microscopy revealed specific stainings for TRPC1, 3, 4, and 6 with predominant intracellular localization [34].
• TRPC1 immunofluorescence was detected in glomeruli and specific tubular cells of the cortex and outer medulla [16].
• Transcriptional expression of TRPC genes was compared by semiquantitative RT-PCR [36].

References