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Molecular Endocrinology, doi:10.1210/me.2004-0450
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Molecular Endocrinology 19 (4): 1078-1087
Copyright © 2005 by The Endocrine Society

ß-Arrestin- and G Protein Receptor Kinase-Mediated Calcium-Sensing Receptor Desensitization

Min Pi, Robert H. Oakley, Diane Gesty-Palmer, Rachael D. Cruickshank, Robert F. Spurney, Louis M. Luttrell and L. Darryl Quarles

The Kidney Institute (M.P., L.D.Q.), Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160; NORAK Biosciences (R.H.O., R.D.C.), Morrisville, North Carolina 27709; Division of Endocrinology (D.G.-P., R.F.S.), Department of Medicine, Duke University Medical Center, Durham, North Carolina 27701; and Division of Endocrinology (L.M.L.), Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425

Address all correspondence and requests for reprints to: L. Darryl Quarles, M.D., Summerfield Endowed Professor of Nephrology, University of Kansas Medical Center, MS 3018, 3901 Rainbow Boulevard, 6018 Wahl Hall East, Kansas City, Kansas 66160. E-mail: dquarles{at}kumc.edu.

Extracellular calcium rapidly controls PTH secretion through binding to the G protein-coupled calcium-sensing receptor (CASR) expressed in parathyroid glands. Very little is known about the regulatory proteins involved in desensitization of CASR. G protein receptor kinases (GRK) and ß-arrestins are important regulators of agonist-dependent desensitization of G protein-coupled receptors. In the present study, we investigated their role in mediating agonist-dependent desensitization of CASR. In heterologous cell culture models, we found that the transfection of GRK4 inhibits CASR signaling by enhancing receptor phosphorylation and ß-arrestin translocation to the CASR. In contrast, we found that overexpression of GRK2 desensitizes CASR by classical mechanisms as well as through phosphorylation-independent mechanisms involving disruption of G{alpha}q signaling. In addition, we observed lower circulating PTH levels and an attenuated increase in serum PTH after hypocalcemic stimulation in ß-arrestin2 null mice, suggesting a functional role of ß-arrestin2-dependent desensitization pathways in regulating CASR function in vivo. We conclude that GRKs and ß-arrestins play key roles in regulating CASR responsiveness in parathyroid glands.




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