The extracellular calcium (Ca2+o)-sensing receptor (CAR) is a key mediator of the direct actions of Ca2+o on the parathyroid and kidney, that play an essential role in the maintenance Ca2+o homeostasis. The CaR is also expressed in numerous other cells where its physiological roles are poorly understood. This receptor likely enables local or systemic levels of Ca2+o to serve widespread, hormone-like or growth factor-like roles in modulating diverse cellular functions. The CaR exerts its biological roles through the intracellular signaling pathways to which it couples. The CaR was initially shown to regulate phospholipases C, D and A2, as well as adenylate cyclase in a G protein-coupled manner. Unfortunately, these signaling pathways could not explain the inverted regulation of PTH secretion by Ca2+o or CaR-mediated regulation of fundamental cellular processes, such as proliferation, differentiation, survival or migration in "non-Ca2+o-homeostatic" cells. Our recent studies reveal several new aspects of CaR-mediated signaling including: (a) identification of new CaR-activated transduction pathways, including ERK1/2, p38 MAPK, and PI-3K cascades, (b) evidence that one mechanism for CaR-mediated activation of MAPK paracrine transactivation of the epidermal growth factor receptor (EGFR), (c) characterization of caveolae as key membrane where the CaR resides and couples to these signaling pathways, and (d) identifying two binding partners of the CaR (filmnin-A and zyxin) that likely serve as scaffolds for CaR-mediated signal activation within the caveolar microenvironment. The overall goals of this proposal are to demonstrate that the CaR mediates activation of the extracellular signal-regulated kinases (ERK1/2) and p38 MAPK cascades as well as PI-3 kinase (PI-3K), to elucidate the role of EGFR transactivation in activating these transduction pathways, to determine the roles of membrane microdomains as well as scaffold proteins in CaR localization and signaling, and to identify the role of these transduction pathways in mediating important CaR-regulated biological responses including hormone secretion, cell proliferation and apoptosis. Accomplishing these goals will provide important insights into how the CaR functions at a cellular and molecular level, how it regulates Ca2+o homeostasis and "non-Ca2+o-homeostatic" physiological processes, and how these processes go awry in various disease states.