The molecular mechanisms underlying the secretion of PTH from the parathyroid chief cells remains a mystery. Despite extensive research, the cellular events which lead to this inhibition remain unknown distal to the activation of the CaR. Recent studies in our laboratory have led to an examination of the MAPK pathways utilized by CaR in controlling cellular events including proliferation, differentiation and peptide secretion. Preliminary experiments on PTH release from bovine parathyroid cells suggest that the p38 kinase pathway is critical for the inhibition of PTH secretion during high-calcium conditions. In addition, recent immunohistochemical studies using confocal microscopy have correlated actin polymerization under the apical membrane with high-calcium conditions with the inhibition of PTH secretion. From this and other evidence, we propose the following model. High calcium activates the CaR, which stimulates the p38 pathway and other transduction events, leading to actin polymerization and inhibition of PTH secretion. We further postulate that activation of filamin-1 leads to CaR-mediated actin polymerization and inhibition of secretion. Parathyroid cells secrete large amounts of PTH under low Ca2+ [o]conditions, often considered the basal state. Issues, which remain poorly understood concerning PTH secretion under low Ca2+[o], include the signal transduction pathways, which support basal PTH secretion and the role of cytoskeleton in active PTH secretion. Recently developed activators and inhibitors of transduction pathways as well as new techniques of molecular biology, which allow genetic manipulation of these pathways, should provide a more comprehensive and detailed study of the transduction pathways in parathyroid cells under low and high Ca2+[o] conditions. Furthermore new understanding of the interplay between lipid raft domains, the cytoskeleton and the secretion cycle suggest a critical role for the microtubular system and caveolin-1 in the regulation of the exocytosis-endocytosis cycle. We postulate the membrane domain bound to CaR and caveolin (the CaR-PTH unit) is free to move along the microtubular and actin filament systems under low Ca2+[o] conditions in a cycle of exocytosis and endocytosis. Phosphorylation of caveolin-1 under high Ca 2+ conditions may anchor the CaR-PTH unit to the plasma membrane, limiting PTH secretion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067155-03
Application #
7023848
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$250,083
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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