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J. Biol. Chem., Vol. 282, Issue 7, 5085-5099, February 16, 2007

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Assembly of an SAP97-AKAP79-cAMP-dependent Protein Kinase Scaffold at the Type 1 PSD-95/DLG/ZO1 Motif of the Human ₁-Adrenergic Receptor Generates a Receptosome Involved in Receptor Recycling and Networking^*

Lidia A. Gardner, Anjaparavanda P. Naren¹, and Suleiman W. Bahouth²

From the Departments of Pharmacology and Physiology, the University of Tennessee Health Sciences Center, Memphis, Tennessee 38163

Appropriate trafficking of the ₁-adrenergic receptor (₁-AR) after agonist-promoted internalization is crucial for the resensitization of its signaling pathway. Efficient recycling of the ₁-AR required the binding of the protein kinase A anchoring protein-79 (AKAP79) to the carboxyl terminus of the ₁-AR (Gardner, L. A., Tavalin, S. A., Goehring, A., Scott, J. D., and Bahouth, S. W. (2006) J. Biol. Chem. 281, 33537-33553). In this study we show that AKAP79 forms a complex with the type 1 PDZ-binding sequence (ESKV) at the extreme carboxyl terminus of the ₁-AR, which is mediated by the membrane-associated guanylate kinase (MAGUK) protein SAP97. Thus, the PDZ and its associated SAP97-AKAP79 complex are involved in targeting the cyclic AMP-dependent protein kinase (PKA) to the ₁-AR. The PDZ and its scaffold were required for efficient recycling of the ₁-AR and for PKA-mediated phosphorylation of the ₁-AR at Ser³¹². Overexpression of the catalytic subunit of PKA or mutagenesis of Ser³¹² to the phosphoserine mimic aspartic acid both rescued the recycling of the trafficking-defective ₁-AR PDZ mutant. Thus, trafficking signals transmitted from the PDZ-associated scaffold in the carboxyl terminus of the ₁-AR to Ser³¹² in the 3rd intracellular loop (3rd IC) were paramount in setting the trafficking itinerary of the ₁-AR. The data presented here show that a novel ₁-adrenergic receptosome is organized at the ₁-AR PDZ to generate a scaffold essential for trafficking and networking of the ₁-AR.

Received for publication, September 15, 2006 , and in revised form, November 27, 2006.

^* This work was supported by Grant-in-aid 6071785 from the Southeastern Affiliate of the American Heart Association (to S. W. B.) and by an NIDDK grant from the National Institutes of Health (to A. P. N.). 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.

¹ Career investigator of the American Lung Association.

² To whom correspondence should be addressed: Dept. of Pharmacology, the University of Tennessee Health Sciences Center, 874 Union Ave., Memphis, TN 38163. Tel.: 901-448-1503; Fax: 901-448-7206; E-mail: sbahouth{at}utmem.edu.

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