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J. Biol. Chem., Vol. 283, Issue 17, 11445-11452, April 25, 2008

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AKAP79 Selectively Enhances Protein Kinase C Regulation of GluR1 at a Ca²⁺-Calmodulin-dependent Protein Kinase II/Protein Kinase C Site^*

From the Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Enhancement of AMPA receptor activity in response to synaptic plasticity inducing stimuli may arise, in part, through phosphorylation of the GluR1 AMPA receptor subunit at Ser-831. This site is a substrate for both Ca²⁺-calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC). However, neuronal protein levels of CaMKII may exceed those of PKC by an order of magnitude. Thus, it is unclear how PKC could effectively regulate this common target site. The multivalent neuronal scaffold A-kinase-anchoring protein 79 (AKAP79) is known to bind PKC and is linked to GluR1 by synapse-associated protein 97 (SAP97). Here, biochemical studies demonstrate that AKAP79 localizes PKC activity near the receptor, thus accelerating Ser-831 phosphorylation. Complementary electrophysiological studies indicate that AKAP79 selectively shifts the dose-dependence for PKC modulation of GluR1 receptor currents 20-fold, such that low concentrations of PKC are as effective as much higher CaMKII concentrations. By boosting PKC activity near a target substrate, AKAP79 provides a mechanism to overcome limitations in kinase abundance thereby ensuring faithful signal propagation and efficient modification of AMPA receptor-mediated responses.

Received for publication, November 12, 2007 , and in revised form, February 22, 2008.

^* This work was supported by Grant NS46661 from the National Institutes of Health and by start-up funds provided by the University of Tennessee Health Science Center and the UTHSC Neurobiology of Brain Disease Center of Excellence. 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 To whom correspondence should be addressed: Dept. of Pharmacology, University of Tennessee Health Science Center, 874 Union Ave., Memphis, TN 38163. Tel.: 901-448-3007; Fax: 901-448-7206; E-mail: stavalin{at}utmem.edu.

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