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Phosphorylation of G₁₁ Protein Contributes to Agonist-Induced Desensitization of 5-HT_2A Receptor Signaling

Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois

Agonist treatment causes desensitization of many G proteincoupled receptor systems. Recent advances have delineated changes in receptors in the desensitization response; however, the role of G proteins remains unclear. We investigated the role of phosphorylation of G_q/11 proteins in agonist-induced desensitization of serotonin 2A (5-HT_2A) receptors. In an embryonic rat cortical cell line (A1A1v), 24-h treatment with 100 nM (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), a 5-HT_2A/2C receptor agonist, decreased DOI-stimulated inositol phosphate accumulation and increased the phosphorylation of G_q/11 proteins, as demonstrated by immunoprecipitation of G_q/11 and both incorporation of ³²P phosphate and labeling with a S/T/Y phosphorylation-dependent antibody. Treatment with DOI for 30 min induced desensitization but did not increase phosphorylation of G_q/11 proteins, suggesting that different mechanisms are involved in desensitization after short- and long-term treatments. Mutation of S154A in a protein kinase C (PKC) and calcium/calmodulin dependent kinase (CaMK) consensus site in G₁₁ significantly reduced DOI-stimulated phosphorylation of G₁₁ and DOI-induced desensitization of 5-HT_2A receptor signaling. Inhibition of PKC and CaMK attenuated phosphorylation of G_q/11 proteins and DOI-induced desensitization of 5-HT_2A receptors. Expression of G₁₁ S154D, a phosphorylation mimic, reduced DOI-stimulated inositol phosphate accumulation. DOI treatment for 24 h also produced heterologous desensitization, as indicated by decreased bradykinin-stimulated inositol phosphate accumulation. These data suggest that phosphorylation of G₁₁ protein by PKC and CaMK contributes to agonistinduced homologous desensitization of 5-HT_2A receptor signaling as well as heterologous desensitization. The phosphorylation of G protein represents a novel mechanism involved in regulation of receptor signaling and agonist-induced desensitization of G protein-coupled receptors.

Address correspondence to: Dr. Nancy A. Muma, Department of Pharmacology Loyola University Chicago, Stritch School of Medicine, 2160 South First Avenue, Maywood, IL 60153. E-mail: nmuma{at}lumc.edu

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