AKAP79 Interacts with Multiple Adenylyl Cyclase (AC) Isoforms and Scaffolds AC5 and-6 to alpha-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) Receptors

作者：Efendiev Riad; Samelson Bret K; Nguyen Bao T; Phatarpekar Prasad V; Baameur Faiza; Scott John D; Dessauer Carmen W^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285(19): 14450-14458.

DOI：10.1074/jbc.M110.109769

Spatiotemporal specificity of cAMP action is best explained by targeting protein kinase A (PKA) to its substrates by A-kinase-anchoring proteins (AKAPs). At synapses in the brain, AKAP79/150 incorporates PKA and other regulatory enzymes into signal transduction networks that include beta-adrenergic receptors, alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA), and N-methyl-D-aspartic acid receptors. We previously showed that AKAP79/150 clusters PKA with type 5 adenylyl cyclase (AC5) to assemble a negative feedback loop in which the anchored kinase phosphorylates AC5 to dynamically suppress cAMP synthesis. We now show that AKAP79 can associate with multiple AC isoforms. The N-terminal regions of AC5, -6, and -9 mediate this protein-protein interaction. Mapping studies located a reciprocal binding surface between residues 77-108 of AKAP79. Intensity-and lifetime-based fluorescence resonance energy transfer demonstrated that deletion of AKAP79(77-108) region abolished AC5-AKAP79 interaction in living cells. The addition of the AKAP79(77-153) polypeptide fragment uncouples AC5/6 interactions with the anchoring protein and prevents PKA-mediated inhibition of AC activity in membranes. Use of the AKAP79(77-153) polypeptide fragment in brain extracts from wild-type and AKAP150(-/-) mice reveals that loss of the anchoring protein results in decreased AMPA receptor-associated AC activity. Thus, we propose that AKAP79/150 mediates protein-protein interactions that place AC5 in proximity to synaptic AMPA receptors.

• 出版日期2010-5-7