FUNCTIONAL CALCIUM-SENSING RECEPTORS IN RAT FIBROBLASTS ARE REQUIRED FOR ACTIVATION OF SRC KINASE AND MITOGEN-ACTIVATED PROTEIN-KINASE IN RESPONSE TO EXTRACELLULAR CALCIUM

Changes in the concentration of extracellular calcium can affect the b alance between proliferation and differentiation in several cell types , including keratinocytes, breast epithelial cells, and fibroblasts, T his report demonstrates that elevation of extracellular calcium stimul ates proliferation-associated signaling pathways in rat fibroblasts an d implicates calcium-sensing receptors (CaR) as mediators of this resp onse, Rat-1 fibroblasts express CaR mRNA and protein and respond to kn own agonists of the CaR with increased IP3 production and release of i ntracellular calcium, Agonists of the CaR can stimulate increased c-SR C kinase activity and increased extracellular signal-regulated kinase 1/mitogen-activated protein kinase activity, Both of the increases in SRC activity and mitogen-activated protein kinase activation are block ed in the presence of a nonfunctional mutant of the CaR, R796W, Prolif eration of wild-type Rat-1 cells is sensitive to changes in extracellu lar calcium, but expression of the nonfunctional CaR mutant or inhibit ion of the calcium-dependent increase in SRC kinase activity block the proliferative response to calcium. These results provide evidence of a novel signal transduction pathway modulating the response of fibrobl asts to extracellular calcium and imply that calcium-sensing receptors may play a role in regulating cell growth in response to extracellula r calcium, in addition to their well known function in systemic calciu m homeostasis.