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This version published online on January 6, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0450
A more recent version of this article appeared on April 1, 2005
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Submitted on November 8, 2004
Accepted on December 27, 2004

{beta}-Arrestin- and GRK-Mediated CASR 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, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.; NORAK Biosciences, 7030 Kit Creek Road, Morrisville, NC, USA; Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC, USA; Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

* To whom correspondence should be addressed. E-mail: dquarles{at}kumc.edu.

Extracellular calcium rapidly controls PTH secretion through binding to the G-protein coupled 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 {beta}-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 {beta}-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 {beta}-arrestin2 null mice, suggesting a functional role of {beta}-arrestin2-dependent desensitization pathways in regulating CASR function in vivo. We conclude that GRKs and {beta}-arrestins play key roles in regulating CASR responsiveness in parathyroid glands.




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