Interaction with AKAP79 modifies the cellular pharmacology of PKC.
A-kinase anchoring proteins (AKAPs) coordinate cell signaling events. AKAP79 brings together different combinations of enzyme binding partners to customize the regulation of effector proteins. In neurons, muscarinic agonists mobilize an AKAP79-anchored pool of PKC that phosphorylates the KCNQ2 subunit of the M channel. This inhibits potassium permeability to enhance neuronal excitability. Using a dual fluorescent imaging/patch-clamp technique, we visualized AKAP79-anchored PKC phosphorylation of the kinase activity reporter CKAR concurrently with electrophysiological changes in KCNQ2 channels to show that AKAP79 synchronizes both signaling events to optimize the attenuation of M currents. AKAP79 also protects PKC from certain ATP-competitive inhibitors. Related studies suggest that context-dependent protein-protein interactions alter the susceptibility of another protein kinase, PDK1, to ATP analog inhibitors. This implies that intracellular binding partners not only couple individual molecular events in a cell signaling process but can also change the pharmacological profile of certain protein kinases.
Hoshi
Naoto
N
Department of Pharmacology, 360 Med Surge II, University of California, Irvine, Irvine, CA 92697, USA.
Langeberg
Lorene K
LK
Gould
Christine M
CM
Newton
Alexandra C
AC
Scott
John D
JD
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009116:Muscarine / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
D054758:A Kinase Anchor Proteins; D051658:KCNQ2 Potassium Channel; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D009116:Muscarine; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C