Beta-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitization.
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 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 Galphaq 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.
Pi
Min
M
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Oakley
Robert H
RH
Gesty-Palmer
Diane
D
Cruickshank
Rachael D
RD
Spurney
Robert F
RF
Luttrell
Louis M
LM
Quarles
L Darryl
LD
D000595:Amino Acid Sequence; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation; D054771:G-Protein-Coupled Receptor Kinase 4; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D010280:Parathyroid Glands / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071557:beta-Arrestins
D019390:Arrestins; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D000071557:beta-Arrestins; D017346:Protein Serine-Threonine Kinases; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human; C517853:GRK4 protein, mouse; D002118:Calcium