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. 2003 Oct;64(4):890-904.
doi: 10.1124/mol.64.4.890.

Agonist- and protein kinase C-induced phosphorylation have similar functional consequences for gastrin-releasing peptide receptor signaling via Gq

Roxanne A Ally  1 , Kirk L Ives, Elie Traube, Iman Eltounsi, Pei-Wen Chen, Patrick J Cahill, James F Battey, Mark R Hellmich, Glenn S Kroog
Affiliations

Agonist- and protein kinase C-induced phosphorylation have similar functional consequences for gastrin-releasing peptide receptor signaling via Gq

Roxanne A Ally et al. Mol Pharmacol. 2003 Oct.

Abstract

Acute desensitization of many guanine nucleotide-binding protein-coupled receptors (GPCRs) requires receptor phosphorylation and subsequent binding of an arrestin. GPCRs are substrates for phosphorylation by several classes of kinases. Gastrin-releasing peptide receptor (GRPr) is phosphorylated by a kinase other than protein kinase C (PKC) after exposure to agonist and is also a substrate for PKC-dependent phosphorylation after treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA). Using GRPr mutants, we examined receptor domains required for agonist- and TPA-induced phosphorylation of GRPr and consequences of these phosphorylation events on GRPr signaling via Gq. Agonist- and TPA-stimulated GRPr phosphorylation in cells require an intact carboxyl terminal domain (CTD). GRPr is phosphorylated in vitro by GPCR kinase 2 (GRK2) and multiple PKC isoforms. An intact DRY motif is required for agonist-stimulated phosphorylation in cells, and agonist-dependent GRK2 phosphorylation in vitro. Although GRPr CTD mutants do not show enhanced in vitro coupling to Gq relative to intact GRPr, CTD mutants have more potent Gq-dependent signaling in cells. Acute desensitization involves CTD-independent processes because desensitization can precede ligand binding in intact GRPr and CTD mutants. TPA-mediated impairment of GRPr-Gq signaling in cells also requires an intact CTD. Similar to GRK2 phosphorylation, PKC phosphorylation reduces GRPr-Gq coupling by approximately 80% in vitro. Arrestin translocation to plasma membrane requires agonist, an intact DRY motif, and GRPr phosphorylation. Therefore, agonist- and PKC-induced GRPr phosphorylation sites are in nearby regions of the receptor, and phosphorylation at both sites has similar functional consequences for Gq signaling.

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