β-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitazation

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

Research output: Contribution to journalArticle

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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 β-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 β-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 Gαq signaling. In addition, we observed lower circulating PTH levels and an attenuated increase in serum PTH after hypocalcemic stimulation in β-arrestin2 null mice, suggesting a functional role of β-arrestin2-dependent desensitization pathways in regulating CASR function in vivo. We conclude that GRKs and β-arrestins play key roles in regulating CASR responsiveness in parathyroid glands.

Original languageEnglish (US)
Pages (from-to)1078-1087
Number of pages10
JournalMolecular Endocrinology
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2005

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Arrestin
Calcium-Sensing Receptors
Cyclic GMP-Dependent Protein Kinases
Arrestins
Parathyroid Glands
Phosphorylation
G-Protein-Coupled Receptors
GTP-Binding Proteins
Transfection
Cell Culture Techniques
Calcium

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

Pi, M., Oakley, R. H., Gesty-Palmer, D., Cruickshank, R. D., Spurney, R. F., Luttrell, L. M., & Quarles, L. (2005). β-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitazation. Molecular Endocrinology, 19(4), 1078-1087. https://doi.org/10.1210/me.2004-0450

β-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitazation. / Pi, Min; Oakley, Robert H.; Gesty-Palmer, Diane; Cruickshank, Rachael D.; Spurney, Robert F.; Luttrell, Louis M.; Quarles, Leigh.

In: Molecular Endocrinology, Vol. 19, No. 4, 01.04.2005, p. 1078-1087.

Research output: Contribution to journalArticle

Pi, M, Oakley, RH, Gesty-Palmer, D, Cruickshank, RD, Spurney, RF, Luttrell, LM & Quarles, L 2005, 'β-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitazation', Molecular Endocrinology, vol. 19, no. 4, pp. 1078-1087. https://doi.org/10.1210/me.2004-0450
Pi M, Oakley RH, Gesty-Palmer D, Cruickshank RD, Spurney RF, Luttrell LM et al. β-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitazation. Molecular Endocrinology. 2005 Apr 1;19(4):1078-1087. https://doi.org/10.1210/me.2004-0450
Pi, Min ; Oakley, Robert H. ; Gesty-Palmer, Diane ; Cruickshank, Rachael D. ; Spurney, Robert F. ; Luttrell, Louis M. ; Quarles, Leigh. / β-arrestin- and G protein receptor kinase-mediated calcium-sensing receptor desensitazation. In: Molecular Endocrinology. 2005 ; Vol. 19, No. 4. pp. 1078-1087.
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