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

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 Gq 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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