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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012641-04
Application #
6523851
Study Section
Special Emphasis Panel (ZRG1-GRM (03))
Program Officer
Kousvelari, Eleni
Project Start
1999-08-01
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
4
Fiscal Year
2002
Total Cost
$320,906
Indirect Cost
Name
University of Delaware
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
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Shao, Ying; Alicknavitch, Michael; Farach-Carson, Mary C (2005) Expression of voltage sensitive calcium channel (VSCC) L-type Cav1.2 (alpha1C) and T-type Cav3.2 (alpha1H) subunits during mouse bone development. Dev Dyn 234:54-62
Bergh, Joel J; Xu, Yihuan; Farach-Carson, Mary C (2004) Osteoprotegerin expression and secretion are regulated by calcium influx through the L-type voltage-sensitive calcium channel. Endocrinology 145:426-36
Farach-Carson, Mary C; Bergh, Joel J; Xu, Yihuan (2004) Integrating rapid responses to 1,25-dihydroxyvitamin D3 with transcriptional changes in osteoblasts: Ca2+ regulated pathways to the nucleus. Steroids 69:543-7

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