Calcium signals in target cells, including osteoblasts, serve as early effectors of external stimuli, including those that are either hormonal or mechanical in nature. For bone, these calcium signals play a major role in cell growth differentiation and coupling which occur during bone remodeling and ion homeostasis. A key molecule involved in mediating calcium signals is the dihydropyridine-binding, voltage sensitive calcium channel (VSCC) that is located in the plasma membrane. In response to specific stimuli, VSCCs open to allow extracellular calcium to enter the cell. The VSCC itself is a large, multi-subunit protein complex. The ion translocating subunit, alpha, has been cloned from several tissues, where it displays tissue-specific structural and functional properties. The alpha, subunit in osteoblasts has been identified at the functional and molecular level in our laboratory. In this proposal, we provide a logical plan for systematic study of the expression and regulation of the osteoblast VSCC, focusing on the alpha, subunit. The three aims address our basic hypothesis that the VSCC serves a vital function in controlling calcium permeability of the osteoblast plasma membrane during development of calcium signals which occur in response to hormonal or mechanical stimuli. A combination of functional, biochemical, immunological, imaging and molecular biological experiments are proposed. Together, these studies will provide new insights to the expression and function of VSCCs in osteoblasts as they impact on normal bone physiology as well as pathological conditions of bone loss.
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