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J. Biol. Chem., Vol. 278, Issue 27, 24831-24836, July 4, 2003

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Targeting of Protein Kinase A by Muscle A Kinase-anchoring Protein (mAKAP) Regulates Phosphorylation and Function of the Skeletal Muscle Ryanodine Receptor^*

Mary L. Ruehr , Mary A. Russell , Donald G. Ferguson , Manju Bhat ¶, Jianjie Ma ||, Derek S. Damron ¶, John D. Scott ** and Meredith Bond   

From the Department of Molecular Cardiology, Lerner Research Institute and ^¶Department of Anesthesiology Research, Cleveland Clinic Foundation, Cleveland, Ohio 44195, ^||Department of Physiology and Biophysics, The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, ^**Howard Hughes Medical Institute, Vollum Institute, Oregon Health & Sciences University, Portland, Oregon 97201, Department of Physiology and Biophysics, and Department of Anatomy, Case Western Reserve University, Cleveland, Ohio 44106

Protein kinase A anchoring proteins (AKAPs) tether cAMP-dependent protein kinase (PKA) to specific subcellular locations. The muscle AKAP, mAKAP, co-localizes with the sarcoplasmic reticulum Ca²⁺ release channel or ryanodine receptor (RyR). The purpose of this study was to determine whether anchoring of PKA by mAKAP regulates RyR function. Either mAKAP or mAKAP-P, which is unable to anchor PKA, was expressed in CHO cells stably expressing the skeletal muscle isoform of RyR (CHO-RyR1). Immunoelectron microscopy showed that mAKAP co-localized with RyR1 in disrupted skeletal muscle. Following the addition of 10 µM forskolin to activate adenylyl cyclase, RyR1 phosphorylation in CHO-RyR1 cells expressing mAKAP increased by 42.4 ± 6.6% (n = 4) compared with cells expressing mAKAP-P. Forskolin treatment alone did not increase the amplitude of the cytosolic Ca²⁺ transient in CHO-RyR1 cells expressing mAKAP or mAKAP-P; however, forskolin plus 10 mM caffeine elicited a cytosolic Ca²⁺ transient, the amplitude of which increased by 22% (p < 0.05) in RyR1/mAKAP-expressing cells compared with RyR1/mAKAP-P-expressing cells. Therefore, localization of PKA by mAKAP at RyR1 increases both PKA-dependent RyR phosphorylation as well as efflux of Ca²⁺ through the RyR. Therefore, RyR1 function is regulated by mAKAP targeting of PKA, implying an important functional role for PKA phosphorylation of RyR in skeletal muscle.

Received for publication, December 30, 2002 , and in revised form, April 21, 2003.

^* This study was supported in part by National Institutes of Health Grants HL10273 (to M. L. R.), AG15556 and HL69000 (to J. M.), HL065701 (to D. S. D.), DK54441 (to J. D. S.), and AG16613 and HL56256 (to M. B.). 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.

To whom correspondence should be addressed: Dept. of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., NB50, Cleveland, OH 44195. Tel.: 216-444-3734; Fax: 216-444-9263; E-mail: bondm{at}ccf.org.

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