Regulation of Ionotropic Glutamate Receptors

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DESCRIPTION (provided by applicant): The AMPA receptor (AMPAR) subtype of ionotropic glutamate receptors mediates the majority of fast excitatory neurotransmission in the mammalian central nervous system. Activity-dependent modifications in the strength of AMPAR-mediated synaptic transmission are thought to contribute to learning, memory, and neuronal development. Pathophysiologically, these receptors may contribute to neurodegeneration, neurotrauma, pain, psychiatric disorders, and drug abuse. The phosphorylation state of the GluR1 AMPAR subunit appears to be a common target for regulation during these diverse forms of synaptic plasticity. Therefore it is important to understand how intracellular signals are transduced to regulate GluR1 phosphorylation. The A-kinase-anchoring protein AKAP79 (AKAP150 in rodents) associates with several second messenger activated signaling proteins including the cAMP-dependent protein kinase (PKA), the Ca(2+)-dependent protein phosphatase PP2B (calcineurin [CaN]), and the Ca(2+) and phospholipid-dependent protein kinase (PKC) and calmodulin (CaM). AKAP79 is targeted to the GluR1 through interaction with SAP97, a member of the MAGUK family of synaptic scaffolding proteins. Recent data indicates that AKAP79 facilitates PKA-and CaN-mediated regulation of GluR1 AMPA receptors; however, the ability of the remaining components of this complex to regulate AMPARs remains to be fully addressed. Using biochemical, electrophysiological, and molecular methods, we will define how AKAP79 shapes AMPAR-mediated responses by examining: 1) regulation of recombinant GluR1 phosphorylation and function by AKAP79-anchored PKC, 2) the role of Ca(2+)/CaM in AKAP79-mediated modulation of GluR1 and 3) the contribution of AKAP150-anchored PKC towards regulation of native AMPA receptors. Understanding the basic operation of the AKAP79/150 signaling complex may lead to novel therapeutic targets for the treatment of neurological disorders and stroke.