title: M3-muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1.
abstract: The activity of G protein-coupled receptors is regulated via hyper-phosphorylation following agonist stimulation. Despite the universal nature of this regulatory process, the physiological impact of receptor phosphorylation remains poorly studied. To address this question, we have generated a knock-in mouse strain that expresses a phosphorylation-deficient mutant of the M(3)-muscarinic receptor, a prototypical G(q/11)-coupled receptor. This mutant mouse strain was used here to investigate the role of M(3)-muscarinic receptor phosphorylation in the regulation of insulin secretion from pancreatic islets. Importantly, the phosphorylation deficient receptor coupled to G(q/11)-signaling pathways but was uncoupled from phosphorylation-dependent processes, such as receptor internalization and β-arrestin recruitment. The knock-in mice showed impaired glucose tolerance and insulin secretion, indicating that M(3)-muscarinic receptors expressed on pancreatic islets regulate glucose homeostasis via receptor phosphorylation-/arrestin-dependent signaling. The mechanism centers on the activation of protein kinase D1, which operates downstream of the recruitment of β-arrestin to the phosphorylated M(3)-muscarinic receptor. In conclusion, our findings support the unique concept that M(3)-muscarinic receptor-mediated augmentation of sustained insulin release is largely independent of G protein-coupling but involves phosphorylation-/arrestin-dependent coupling of the receptor to protein kinase D1.
authors.affiliation: Department of Cell Physiology and Pharmacology, and Biomedical Services Division, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Kok Choi
authors.initials: KC
authors.lastname: Kong
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Butcher
authors.forename: Phillip
authors.initials: P
authors.lastname: McWilliams
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Tim
authors.initials: T
authors.lastname: Werry
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Rosethorne
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Munson
authors.forename: Hannah A
authors.initials: HA
authors.lastname: Cragg
authors.forename: Alison D
authors.initials: AD
authors.lastname: Smart
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Tobin
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D004789:Enzyme Activation; D005947:Glucose; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D007328:Insulin; D043587:Receptor, Muscarinic M3; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C089212:protein kinase D; D011493:Protein Kinase C; D005947:Glucose