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Volume 270, Number 30, Issue of July 28, pp. 17953-17961, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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Phosphorylation and Desensitization of the Human -Adrenergic Receptor
INVOLVEMENT OF G PROTEIN-COUPLED RECEPTOR KINASES AND cAMP-DEPENDENT PROTEIN KINASE

(Received for publication, February 15, 1995; and in revised form, May 11, 1995)

From the  (1)Howard Hughes Medical Institute, Departments of Medicine (Cardiology), (2)Biochemistry, and (3)Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

Persistent stimulation of the -adrenergic receptor (AR) engenders, within minutes, diminished responsiveness of the AR/adenylyl cyclase signal transduction system. This desensitization remains incompletely defined mechanistically, however. We therefore tested the hypothesis that agonist-induced desensitization of the AR (like that of the related AR) involves phosphorylation of the receptor itself, by cAMP-dependent protein kinase (PKA) and the -adrenergic receptor kinase (ARK1) or other G protein-coupled receptor kinases (GRKs). Both Chinese hamster fibroblast and 293 cells demonstrate receptor-specific desensitization of the AR within 3-5 min. Both cell types also express ARK1 and the associated inhibitory proteins -arrestin-1 and -arrestin-2, as assessed by immunoblotting. Agonist-induced AR desensitization in 293 cells correlates with a 2 ± 0.3-fold increase in phosphorylation of the AR, determined by immunoprecipitation of the AR from cells metabolically labeled with P. This agonist-induced AR phosphorylation derives approximately equally from PKA and GRK activity, as judged by intact cell studies with kinase inhibitors or dominant negative ARK1 (K220R) mutant overexpression. Desensitization, likewise, is reduced by only 50% when PKA is inhibited in the intact cells. Overexpression of rhodopsin kinase, ARK1, ARK2, or GRK5 significantly increases agonist-induced AR phosphorylation and concomitantly decreases agonist-stimulated cellular cAMP production (p < 0.05). Furthermore, purified ARK1, ARK2, and GRK5 all demonstrate agonist-dependent phosphorylation of the AR. Consistent with a GRK mechanism, receptor-specific desensitization of the AR was enhanced by overexpression of -arrestin-1 and -2 in transfected 293 cells. We conclude that rapid agonist-induced desensitization of the AR involves phosphorylation of the receptor by both PKA and at least ARK1 in intact cells. Like the AR, the AR appears to bind either -arrestin-1 or -arrestin-2 and to react with rhodopsin kinase, ARK1, ARK2, and GRK5.

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				M. Oppermann, M. Mack, A. E. I. Proudfoot, and H. Olbrich Differential Effects of CC Chemokines on CC Chemokine Receptor 5 (CCR5) Phosphorylation and Identification of Phosphorylation Sites on the CCR5 Carboxyl Terminus J. Biol. Chem., March 26, 1999; 274(13): 8875 - 8885. [Abstract] [Full Text] [PDF]

				G. J. Della Rocca, Y. V. Mukhin, M. N. Garnovskaya, Y. Daaka, G. J. Clark, L. M. Luttrell, R. J. Lefkowitz, and J. R. Raymond Serotonin 5-HT1A Receptor-mediated Erk Activation Requires Calcium/Calmodulin-dependent Receptor Endocytosis J. Biol. Chem., February 19, 1999; 274(8): 4749 - 4753. [Abstract] [Full Text] [PDF]

				R.-P. Xiao, P. Avdonin, Y.-Y. Zhou, H. Cheng, S. A. Akhter, T. Eschenhagen, R. J. Lefkowitz, W. J. Koch, and E. G. Lakatta Coupling of ß2-Adrenoceptor to Gi Proteins and Its Physiological Relevance in Murine Cardiac Myocytes Circ. Res., January 22, 1999; 84(1): 43 - 52. [Abstract] [Full Text] [PDF]

				K. M. Anderson, A. D. Eckhart, R. N. Willette, and W. J. Koch The Myocardial ß-Adrenergic System in Spontaneously Hypertensive Heart Failure (SHHF) Rats Hypertension, January 1, 1999; 33(1): 402 - 407. [Abstract] [Full Text] [PDF]

				V. Beaumont, M. B. Hepworth, J. S. Luty, E. Kelly, and G. Henderson Somatostatin Receptor Desensitization in NG108-15 Cells. A CONSEQUENCE OF RECEPTOR SEQUESTRATION J. Biol. Chem., December 11, 1998; 273(50): 33174 - 33183. [Abstract] [Full Text] [PDF]

				R. D. Smith, L. Hunyady, J. A. Olivares-Reyes, B. Mihalik, S. Jayadev, and K. J. Catt Agonist-Induced Phosphorylation of the Angiotensin AT1a Receptor Is Localized to a Serine/Threonine-Rich Region of Its Cytoplasmic Tail Mol. Pharmacol., December 1, 1998; 54(6): 935 - 941. [Abstract] [Full Text]

				R. T. Premont, A. Claing, N. Vitale, J. L. R. Freeman, J. A. Pitcher, W. A. Patton, J. Moss, M. Vaughan, and R. J. Lefkowitz beta 2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein PNAS, November 24, 1998; 95(24): 14082 - 14087. [Abstract] [Full Text] [PDF]

				G. Iaccarino, E. D. Tomhave, R. J. Lefkowitz, and W. J. Koch Reciprocal In Vivo Regulation of Myocardial G Protein–Coupled Receptor Kinase Expression by ß-Adrenergic Receptor Stimulation and Blockade Circulation, October 27, 1998; 98(17): 1783 - 1789. [Abstract] [Full Text] [PDF]

				G. Iaccarino, H. A. Rockman, K. F. Shotwell, E. D. Tomhave, and W. J. Koch Myocardial overexpression of GRK3 in transgenic mice: evidence for in vivo selectivity of GRKs Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1298 - H1306. [Abstract] [Full Text] [PDF]

				Z.-J. Cheng, Q.-M. Yu, Y.-L. Wu, L. Ma, and G. Pei Selective Interference of beta -Arrestin 1 with kappa  and delta  but Not µ Opioid Receptor/G Protein Coupling J. Biol. Chem., September 18, 1998; 273(38): 24328 - 24333. [Abstract] [Full Text] [PDF]

				E. M. Smyth, W. H. Li, and G. A. FitzGerald Phosphorylation of the Prostacyclin Receptor during Homologous Desensitization. A CRITICAL ROLE FOR PROTEIN KINASE C J. Biol. Chem., September 4, 1998; 273(36): 23258 - 23266. [Abstract] [Full Text] [PDF]

				R. B. Penn, R. A. Panettieri Jr., and J. L. Benovic Mechanisms of Acute Desensitization of the beta 2AR-Adenylyl Cyclase Pathway in Human Airway Smooth Muscle Am. J. Respir. Cell Mol. Biol., August 1, 1998; 19(2): 338 - 348. [Abstract] [Full Text]

				H. A. Rockman, D.-J. Choi, S. A. Akhter, M. Jaber, B. Giros, R. J. Lefkowitz, M. G. Caron, and W. J. Koch Control of Myocardial Contractile Function by the Level of beta -Adrenergic Receptor Kinase 1 in Gene-targeted Mice J. Biol. Chem., July 17, 1998; 273(29): 18180 - 18184. [Abstract] [Full Text] [PDF]

				R. D. Smith, A. J. Baukal, A. Zolyomi, Z. Gaborik, L. Hunyady, L. Sun, M. Zhang, H.-C. Chen, and K. J. Catt Agonist-Induced Phosphorylation of the Endogenous AT1 Angiotensin Receptor in Bovine Adrenal Glomerulosa Cells Mol. Endocrinol., May 1, 1998; 12(5): 634 - 644. [Abstract] [Full Text]

				J. D. Neill, L. W. Duck, L. C. Musgrove, and J. C. Sellers Potential Regulatory Roles for G Protein-Coupled Receptor Kinases and {beta}-Arrestins in Gonadotropin-Releasing Hormone Receptor Signaling Endocrinology, April 1, 1998; 139(4): 1781 - 1788. [Abstract] [Full Text] [PDF]

				M. A. Shetzline, R. T. Premont, J. K. L. Walker, S. R. Vigna, and M. G. Caron A Role for Receptor Kinases in the Regulation of Class II G Protein-coupled Receptors. PHOSPHORYLATION AND DESENSITIZATION OF THE SECRETIN RECEPTOR J. Biol. Chem., March 20, 1998; 273(12): 6756 - 6762. [Abstract] [Full Text] [PDF]

				N. Ishizaka, R. W. Alexander, J. B. Laursen, H. Kai, T. Fukui, M. Oppermann, R. J. Lefkowitz, P. R. Lyons, and K. K. Griendling G Protein-coupled Receptor Kinase 5 in Cultured Vascular Smooth Muscle Cells and Rat Aorta. REGULATION BY ANGIOTENSIN II AND HYPERTENSION J. Biol. Chem., December 19, 1997; 272(51): 32482 - 32488. [Abstract] [Full Text] [PDF]

				J. G. Krupnick, F. Santini, A. W. Gagnon, J. H. Keen, and J. L. Benovic Modulation of the Arrestin-Clathrin Interaction in Cells. CHARACTERIZATION OF beta -ARRESTIN DOMINANT-NEGATIVE MUTANTS J. Biol. Chem., December 19, 1997; 272(51): 32507 - 32512. [Abstract] [Full Text] [PDF]

				David. A. Conner, M. A. Mathier, R. M. Mortensen, M. Christe, S. F. Vatner, C. E. Seidman, and J. G. Seidman ß-Arrestin1 Knockout Mice Appear Normal but Demonstrate Altered Cardiac Responses to ß-Adrenergic Stimulation Circ. Res., December 19, 1997; 81(6): 1021 - 1026. [Abstract] [Full Text]

				H. Althoefer, P. Eversole-Cire, and M. I. Simon Constitutively Active Galpha q and Galpha 13 Trigger Apoptosis through Different Pathways J. Biol. Chem., September 26, 1997; 272(39): 24380 - 24386. [Abstract] [Full Text] [PDF]

				N. J. Freedman, A. S. Ament, M. Oppermann, R. H. Stoffel, S. T. Exum, and R. J. Lefkowitz Phosphorylation and Desensitization of Human Endothelin A and B Receptors. EVIDENCE FOR G PROTEIN-COUPLED RECEPTOR KINASE SPECIFICITY J. Biol. Chem., July 11, 1997; 272(28): 17734 - 17743. [Abstract] [Full Text] [PDF]

				E. R. Prossnitz Desensitization of N-Formylpeptide Receptor-mediated Activation Is Dependent upon Receptor Phosphorylation J. Biol. Chem., June 13, 1997; 272(24): 15213 - 15219. [Abstract] [Full Text] [PDF]

				H. Yang, D. Lu, G. P. Vinson, and M. K. Raizada Involvement of MAP Kinase in Angiotensin II-Induced Phosphorylation and Intracellular Targeting of Neuronal AT1 Receptors J. Neurosci., March 1, 1997; 17(5): 1660 - 1669. [Abstract] [Full Text] [PDF]

				K. M. Krueger, Y. Daaka, J. A. Pitcher, and R. J. Lefkowitz The Role of Sequestration in G Protein-coupled Receptor Resensitization. REGULATION OF beta 2-ADRENERGIC RECEPTOR DEPHOSPHORYLATION BY VESICULAR ACIDIFICATION J. Biol. Chem., January 3, 1997; 272(1): 5 - 8. [Abstract] [Full Text] [PDF]

				E. M. Smyth, P. V. Nestor, and G. A. FitzGerald Agonist-dependent Phosphorylation of an Epitope-tagged Human Prostacyclin Receptor J. Biol. Chem., December 27, 1996; 271(52): 33698 - 33704. [Abstract] [Full Text] [PDF]

				R. Vezza, A. Habib, H. Li, J. A. Lawson, and G. A. FitzGerald Regulation of Cyclooxygenases by Protein Kinase C. EVIDENCE AGAINST THE IMPORTANCE OF DIRECT ENZYME PHOSPHORYLATION J. Biol. Chem., November 22, 1996; 271(47): 30028 - 30033. [Abstract] [Full Text] [PDF]