Department of Pharmacology, University of California, Irvine, CA 92697, USA.
EMBO J. 2012 May 29;31(14):3147-56. doi: 10.1038/emboj.2012.156.
Several neurotransmitters, including acetylcholine, regulate neuronal tone by suppressing a non-inactivating low-threshold voltage-gated potassium current generated by the M-channel. Agonist dependent control of the M-channel is mediated by calmodulin, activation of anchored protein kinase C (PKC), and depletion of the phospholipid messenger phosphatidylinositol 4,5-bisphosphate (PIP2). In this report, we show how this trio of second messenger responsive events acts synergistically and in a stepwise manner to suppress activity of the M-current. PKC phosphorylation of the KCNQ2 channel subunit induces dissociation of calmodulin from the M-channel complex. The calmodulin-deficient channel has a reduced affinity towards PIP2. This pathway enhances the effect of concomitant reduction of PIP2, which leads to disruption of the M-channel function. These findings clarify how a common lipid cofactor, such as PIP2, can selectively regulate ion channels.
几种神经递质，包括乙酰胆碱，通过抑制由 M 通道产生的非失活的低阈值电压门控钾电流来调节神经元的张力。M 通道的激动剂依赖性控制是通过钙调蛋白、锚定蛋白激酶 C（PKC）的激活和磷脂信使二磷酸肌醇 4,5-二磷酸（PIP2）的耗竭来介导的。在本报告中，我们展示了这三信使反应事件如何协同作用并逐步抑制 M 电流的活性。PKC 对 KCNQ2 通道亚基的磷酸化诱导钙调蛋白从 M 通道复合物中解离。钙调蛋白缺陷通道对 PIP2 的亲和力降低。这条途径增强了同时减少 PIP2 的效果，导致 M 通道功能中断。这些发现阐明了常见的脂质辅助因子（如 PIP2）如何选择性地调节离子通道。
