QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.105.019901v1 69/3/759    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Related articles in MolPharm Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rankin, M. L. Articles by Sibley, D. R. Search for Related Content PubMed PubMed Citation Articles by Rankin, M. L. Articles by Sibley, D. R.

The D₁ Dopamine Receptor Is Constitutively Phosphorylated by G Protein-Coupled Receptor Kinase 4

Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.L.R., P.S.M., D.M.C., D.R.S.); and Department of Pediatrics, Georgetown University Medical Center, Washington DC (Z.W., P.A.J.)

G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate agonist-activated GPCRs, initiating their homologous desensitization. In this article, 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 isoform of GRK4; the , , and isoforms are ineffective in this regard. Mutational analysis reveals that the constitutive phosphorylation mediated by GRK4 is restricted to the distal region of the carboxyl terminus of the receptor, specifically to residues Thr428 and Ser431. Phosphorylation of the D₁ receptor by GRK4 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 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 does not alter agonist-induced desensitization of the receptor because dopamine pretreatment produced a similar decrease in cAMP accumulation in control cells versus cells expressing GRK4. 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.

Address correspondence to: Dr. David R. Sibley, Molecular Neuropharmacology Section, NINDS/NIH, 5625 Fishers Lane, Room 4S-04, MSC 9405, Bethesda, MD 20892-9405. E-mail: sibley{at}helix.nih.gov

Related articles in MolPharm:

Novel Features of G Protein-Coupled Receptor Kinase 4

Kim A. Neve
MolPharm 2006 69: 673-676. [Abstract] [Full Text]  

This article has been cited by other articles:

				J. A. Staessen, T. Kuznetsova, H. Zhang, M. Maillard, M. Bochud, S. Hasenkamp, J. Westerkamp, T. Richart, L. Thijs, X. Li, et al. Blood Pressure and Renal Sodium Handling in Relation to Genetic Variation in the DRD1 Promoter and GRK4 Hypertension, June 1, 2008; 51(6): 1643 - 1650. [Abstract] [Full Text] [PDF]

				M. M. C. Kong, A. Hasbi, M. Mattocks, T. Fan, B. F. O'Dowd, and S. R. George Regulation of D1 Dopamine Receptor Trafficking and Signaling by Caveolin-1 Mol. Pharmacol., November 1, 2007; 72(5): 1157 - 1170. [Abstract] [Full Text] [PDF]

				A. A. Banday, F. R. Fazili, and M. F. Lokhandwala Insulin causes renal dopamine D1 receptor desensitization via GRK2-mediated receptor phosphorylation involving phosphatidylinositol 3-kinase and protein kinase C Am J Physiol Renal Physiol, September 1, 2007; 293(3): F877 - F884. [Abstract] [Full Text] [PDF]

				A. A. Banday and M. F. Lokhandwala Oxidative stress reduces renal dopamine D1 receptor-Gq/11{alpha} G protein-phospholipase C signaling involving G protein-coupled receptor kinase 2 Am J Physiol Renal Physiol, July 1, 2007; 293(1): F306 - F315. [Abstract] [Full Text] [PDF]

				Z. Wang, I. Armando, L. D. Asico, C. Escano, X. Wang, Q. Lu, R. A. Felder, C. G. Schnackenberg, D. R. Sibley, G. M. Eisner, et al. The elevated blood pressure of human GRK4{gamma} A142V transgenic mice is not associated with increased ROS production Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2083 - H2092. [Abstract] [Full Text] [PDF]

				K. A. Neve Novel Features of G Protein-Coupled Receptor Kinase 4 Mol. Pharmacol., March 1, 2006; 69(3): 673 - 676. [Abstract] [Full Text] [PDF]