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Agonist- and Protein Kinase C-Induced Phosphorylation Have Similar Functional Consequences for Gastrin-Releasing Peptide Receptor Signaling via G_q

Departments of Medicine (G.S.K) and Molecular Pharmacology (G.S.K., R.A.A., E.T., I.E., P.-W.C.), Albert Einstein College of Medicine, Bronx, New York; Department of Surgery, University of Texas Medical Branch, Galveston, Texas (K.L.I., M.R.H.); and the Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland (P.J.C., J.F.B.)

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 G_q. 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 G_q relative to intact GRPr, CTD mutants have more potent G_q-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-G_q signaling in cells also requires an intact CTD. Similar to GRK2 phosphorylation, PKC phosphorylation reduces GRPr-G_q 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 G_q signaling.

Address correspondence to: Dr. Glenn S. Kroog, Department of Molecular Pharmacology, Chanin 302D, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail: gkroog{at}aecom.yu.edu

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