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

Abstract

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.

Delineation of a Conserved Arrestin-Biased Signaling Repertoire In Vivo

“…Compared with WT, adult arrestin3 knockout (Arrb2KO) null mice exhibit normal skeletal morphology and similar whole-body bone-mineral density (Gesty-Palmer et al, 2009). As might be expected given that ablation of arrestin3 should globally impair GPCR desensitization, circulating endogenous PTH levels are suppressed in the Arrb2KO background (Pi et al, 2005), and dynamic indices of bone turnover indicate a higher basal rate of both bone formation and bone resorption (Gesty-Palmer et al, 2009). The effects of Arrb2KO on basal bone transcription are included in Supplemental Table 38 (see also Gesty-Palmer et al, 2013).…”

Novel Role of the Calcium-Sensing Receptor in Blood Pressure Modulation

“…Although the CaR is believed to desensitize very slowly, ß-arrestins and G protein-coupled kinases appear to mediate CaR desensitization. 34 In favor of this notion, ß-arrestin 2 null mice appear to have a leftward shift in the calcium-PTH relationship, and this inverse sigmoidal relationship is mediated by the CaR, as mentioned above. Thus, ß-arrestins are also important for regulating CaR function in the parathyroid glands in vivo.…”

Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

“…In vivo, arrestin3-null mice have normal serum calcium levels and grossly normal skeletal structure. Circulating levels of endogenous PTH are suppressed, presumably in compensation for impaired desensitization of PTHstimulated G protein activation (Pi et al, 2005). However the loss of arrestin3 does alter underlying bone metabolism.…”