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J. Biol. Chem., Vol. 283, Issue 13, 8070-8074, March 28, 2008

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Deregulated Protein Kinase A Signaling and Myospryn Expression in Muscular Dystrophy^*

From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215

Alterations in signaling pathway activity have been implicated in the pathogenesis of Duchenne muscular dystrophy, a degenerative muscle disease caused by a deficiency in the costameric protein dystrophin. Accordingly, the notion of the dystrophin-glycoprotein complex, and by extension the costamere, as harboring signaling components has received increased attention in recent years. The localization of most, if not all, signaling enzymes to this subcellular region relies on interactions with scaffolding proteins directly or indirectly associated with the dystrophin-glycoprotein complex. One of these scaffolds is myospryn, a large, muscle-specific protein kinase A (PKA) anchoring protein or AKAP. Previous studies have demonstrated a dysregulation of myospryn expression in human Duchenne muscular dystrophy, suggesting a connection to the pathophysiology of the disorder. Here we report that dystrophic muscle exhibits reduced PKA activity resulting, in part, from severely mislocalized myospryn and the type II regulatory subunit (RII) of PKA. Furthermore, we show that myospryn and dystrophin coimmunoprecipitate in native muscle extracts and directly interact in vitro. Our findings reveal for the first time abnormalities in the PKA signal transduction pathway and myospryn regulation in dystrophin deficiency.

Received for publication, November 21, 2007 , and in revised form, February 1, 2008.

^* This work was supported by grants from the National Institute of Health and the Muscular Dystrophy Association (to F. J. N.) and an Undergraduate Research Opportunities Program (UROP-Boston University) award (to J. A. D.). 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 a supplemental figure, a supplemental table, and supplemental references.

¹ To whom correspondence should be addressed: Dept. of Biology, Boston University, 24 Cummington St., Boston, MA 02215. Tel.: 617-353-2469; Fax: 617-353-6340; E-mail: fnaya{at}bu.edu.

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