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First published on December 7, 2005; DOI: 10.1124/mol.105.019901

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Received for publication October 17, 2005.
Revised December 7, 2005.
Accepted for publication December 7, 2005.

THE D1 DOPAMINE RECEPTOR IS CONSTITUTIVELY PHOSPHORYLATED BY G PROTEIN-COUPLED RECEPTOR KINASE 4: EVIDENCE FOR A NOVEL MECHANISM OF REGULATION

Michele L Rankin 1, Paul S Marinec 1, David M Cabrera 1, Zheng Wang 2, Pedro A Jose 2, David R. Sibley 3*

1 NINDS/NIH 2 Georgetown Univ. Med. Ctr. 3 NINDS/ NIH

* Address correspondence to: E-mail: sibley{at}helix.nih.gov

Abstract

G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate agonist-activated GPCRs, initiating their homologous desensitization. Here, we present data showing that GRK4 constitutively phosphorylates the D1 receptor in the absence of agonist activation. This constitutive phosphorylation is mediated exclusively by the {alpha} isoform of GRK4, as the {beta}, {gamma}, and {delta} isoforms are ineffective in this regard. Mutational analysis reveals that the constitutive phosphorylation mediated by GRK4{alpha} is restricted to the distal region of the carboxyl terminus of the receptor, specifically to residues T428 and S431. Phosphorylation of the D1 receptor by GRK4{alpha} results in a decrease in cAMP accumulation, an increase in receptor internalization, and a decrease in total receptor number - all of which are abolished in a D1 receptor mutant containing T428V and S431A. The increase in internalized D1 receptors induced by GRK4{alpha} phosphorylation is due to enhanced receptor internalization rather than retarded trafficking of newly synthesized receptors to the cell surface. The constitutive phosphorylation of the D1 receptor by GRK4{alpha} does not alter agonist-induced desensitization of the receptor since dopamine pretreatment produced a similar decrease in cAMP accumulation in control cells versus cells expressing GRK4{alpha}. These observations shift the attenuation of D1 receptor signaling from a purely agonist-driven process to one that is additionally modulated by the complement of kinases that are coexpressed in the same cell. Furthermore, our data provide direct evidence that, in contrast to current dogma, GRKs can, at least in some instances, constitutively phosphorylate GPCRs in the absence of agonist activation resulting in constitutive desensitization.


Key words: Dopamine, Gs family, cAMP, Desensitization/uncoupling, GRKs, barrestins, Phosphorylation/Dephosphorylation, Func. analysis receptor/ion channel mutants, Mutagenesis/Chimeric approaches


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