The calcium-sensing receptor (CaR), is a G protein-dependent receptor that responds to increments in extracellular Ca2+ ([Ca2+]o). We previously reported that an increase in [Ca2+]o induced a release of intracellular calcium and Ca2+ entry via store operated channels (SOCs). We also demonstrated that MCF-7 cells express Transient Receptor Potential canonical 1 (TRPC1) channels. Herein, we investigated CaR intracellular signaling pathways and examined the role of TRPC1 in CaR-induced cell proliferation, through the extracellular signal-regulated Kinases 1 & 2 (ERK1/2) pathways. Treatment by [Ca2+]o increased both MCF-7 cell proliferation and TRPC1 expression. Both the [Ca2+]o proliferative effect and TRPC1 protein levels were abolished by the ERK1/2 inhibitors. Moreover, [Ca2+]o failed to increase cell proliferation either in the presence of CaR or TRPC1 siRNAs. Both [Ca2+]o and the selective CaR activator spermine, elicited time and dose-dependent ERK1/2 phosphorylation. ERK1/2 phosphorylation was almost completely inhibited by treatment with the phospholipase C and the protein kinase C inhibitors. Treatment with 2-aminoethoxydiphenyl borate (2-APB), and SKF-96365 or by siTRPC1 diminished both [Ca2+]o- and spermine-stimulated ERK1/2 phosphorylation. Moreover, down-regulation of TRPC1 by siRNA reduced the Ca2+ entry induced by CaR activation. We conclude that the CaR activates ERK1/2 via a PLC/PKC-dependent pathway. Moreover, TRPC1 is required for the ERK1/2 phosphorylation, Ca2+ entry and the CaR-proliferative effect.

Keywords:
CaR, TRPC1, ERK1/2, Breast cancer cells, Cell proliferation
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© 2009 S. Karger AG, Basel
2009
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