The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain.
A-kinase anchoring proteins (AKAPs) influence the spatial and temporal regulation of cAMP signaling events. Anchoring of PKA in proximity to certain adenylyl cyclase (AC) isoforms is thought to enhance the phosphorylation dependent termination of cAMP synthesis. Using a combination of immunoprecipitation and enzymological approaches, we show that the plasma membrane targeted anchoring protein AKAP9/Yotiao displays unique specificity for interaction and the regulation of a variety of AC isoforms. Yotiao inhibits AC 2 and 3, but has no effect on AC 1 or 9, serving purely as a scaffold for these latter isoforms. Thus, Yotiao represents an inhibitor of AC2. The N terminus of AC2 (AC2-NT), which binds directly to amino acids 808-957 of Yotiao, mediates this interaction. Additionally, AC2-NT and Yotiao (808-957) are able to effectively inhibit the association of AC2 with Yotiao and, thus, reverse the inhibition of AC2 by Yotiao in membranes. Finally, disruption of Yotiao-AC interactions gives rise to a 40% increase in brain AC activity, indicating that this anchoring protein functions to directly regulate cAMP production in the brain.
Piggott
Leslie A
LA
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
Bauman
Andrea L
AL
Scott
John D
JD
Dessauer
Carmen W
CW
D054758:A Kinase Anchor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D011485:Protein Binding; D051381:Rats
D054758:A Kinase Anchor Proteins; D000067956:Adenylyl Cyclase Inhibitors; C486537:Akap9 protein, rat; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000262:Adenylyl Cyclases
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