Phosphorylation uncouples the gastrin-releasing peptide receptor from G(q)

Previous work on the desensitization of G protein-coupled receptors has foc used on the role of arrestin binding following receptor phosphorylation. We have examined the hypothesis that phosphorylation alone contributes to des ensitization. In this study we demonstrate that for the G(q)-coupled gastri n-releasing peptide receptor (GRP-R), phosphorylation by GRK2 to a stoichio metry of similar to 1 mol PO4/mol GRP-R is sufficient in the absence of arr estin to reduce the rate of receptor catalyzed G protein activation by appr oximately 80%. Furthermore, GRP-Rs exposed in vivo to agonist are rapidly p hosphorylated to a similar stoichiometry and are desensitized to a similar degree. Finally, the molecular mechanism for both in vitro GRK2-induced and in vivo agonist-induced desensitization is primarily a decrease in the max imum velocity (V-max) for the catalysis of guanine nucleotide exchange by t he GRP-R rather than a change in the affinity of the receptor for the alpha (q) or beta(gamma) subunits. Based on these results, we suggest that, for s ome G protein-coupled receptors, phosphorylation has a role in desensitizat ion that is independent of arrestin.