Department of Pharmacology, 360 Med Surge II, University of California, Irvine, Irvine, CA 92697, USA.
Mol Cell. 2010 Feb 26;37(4):541-50. doi: 10.1016/j.molcel.2010.01.014.
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.
A-激酶锚定蛋白（AKAPs）协调细胞信号事件。AKAP79 将不同的酶结合伙伴组合在一起，定制效应蛋白的调节。在神经元中，毒蕈碱激动剂动员 AKAP79 锚定的 PKC 池，磷酸化 M 通道的 KCNQ2 亚基。这抑制钾通透性以增强神经元兴奋性。使用双荧光成像/膜片钳技术，我们可视化 AKAP79 锚定的 PKC 磷酸化激酶活性报告物 CKAR，同时观察 KCNQ2 通道的电生理变化，表明 AKAP79 同步这两个信号事件，以优化 M 电流的衰减。AKAP79 还保护 PKC 免受某些 ATP 竞争性抑制剂的影响。相关研究表明，上下文相关的蛋白质-蛋白质相互作用改变了另一种蛋白激酶 PDK1 对 ATP 类似物抑制剂的敏感性。这意味着细胞内结合伙伴不仅可以偶联细胞信号过程中的单个分子事件，还可以改变某些蛋白激酶的药理学特性。
