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J. Biol. Chem., Vol. 281, Issue 44, 33537-33553, November 3, 2006

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AKAP79-mediated Targeting of the Cyclic AMP-dependent Protein Kinase to the ₁-Adrenergic Receptor Promotes Recycling and Functional Resensitization of the Receptor^*

Lidia A. Gardner, Steven J. Tavalin, April S. Goehring, John D. Scott, and Suleiman W. Bahouth¹

From the Department of Pharmacology, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163 and the Howard Hughes Medical Institute, Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239

Resensitization of G protein-coupled receptors (GPCR) following prolonged agonist exposure is critical for restoring the responsiveness of the receptor to subsequent challenges by agonist. The 3'-5' cyclic AMP-dependent protein kinase (PKA) and serine 312 in the third intracellular loop of the human ₁-adrenergic receptor (₁-AR) were both necessary for efficient recycling and resensitization of the agonist-internalized ₁-AR (Gardner, L. A., Delos Santos, N. M., Matta, S. G., Whitt, M. A., and Bahouth, S. W. (2004) J. Biol. Chem. 279, 21135-21143). Because PKA is compartmentalized near target substrates by interacting with protein kinase A anchoring proteins (AKAPs), the present study was undertaken to identify the AKAP involved in PKA-mediated phosphorylation of the ₁-AR and in its recycling and resensitization. Here, we report that Ht-31 peptide-mediated disruption of PKA/AKAP interactions prevented the recycling and functional resensitization of heterologously expressed ₁-AR in HEK-293 cells and endogenously expressed ₁-AR in SK-N-MC cells and neonatal rat cortical neurons. Whereas several endogenous AKAPs were identified in HEK-293 cells, small interfering RNA-mediated down-regulation of AKAP79 prevented the recycling of the ₁-AR in this cell line. Co-immunoprecipitations and fluorescence resonance energy transfer (FRET) microscopy experiments in HEK-293 cells revealed that the ₁-AR, AKAP79, and PKA form a ternary complex at the carboxyl terminus of the ₁-AR. This complex was involved in PKA-mediated phosphorylation of the third intracellular loop of the ₁-AR because disruption of PKA/AKAP interactions or small interfering RNA-mediated down-regulation of AKAP79 both inhibited this response. Thus, AKAP79 provides PKA to phosphorylate the ₁-AR and thereby dictate the recycling and resensitization itineraries of the ₁-AR.

Received for publication, February 24, 2006 , and in revised form, July 18, 2006.

^* This work was supported by a grant-in-aid from the Southeastern affiliate of the American Heart Association and National Institutes of Health Grants HL-71419 (to S. W. B.), NS-46661 (to S. J. T.), and GM-48231 (to J. D. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental movie 1.

¹ To whom correspondence should be addressed: 874 Union Ave., Memphis, TN 38163. Tel.: 901-448-1503; Fax: 901-448-7206; E-mail: sbahouth{at}utmem.edu.

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