Modulation of SK2 by protein kinase CK2 and PP2a

蛋白激酶 CK2 和 PP2a 对 SK2 的调节

• 批准号: 7155147
• 负责人: Duane M Allen
• 金额: $ 4.17万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155147
• 关键词: Lentivirus; NMDA receptors; action potentials; brain electrical activity; brain metabolism; calcium flux; calmodulin; casein kinase; enzyme activity; genetically modified animals; hippocampus; laboratory mouse; neural plasticity; neurochemistry; neurogenetics; neuroregulation; phosphoprotein phosphatase; phosphorylation; potassium channel; predoctoral investigator; tissue /cell culture; transfection /expression vector; voltage /patch clamp

DESCRIPTION (provided by applicant): SK channels influence neuronal excitability, synaptic plasticity, and memory acquisition. SK channels are gated solely by intracellular Ca2+ ions and Ca2+ gating is endowed to SK channels by a constitutive interaction with the prototypic Ca2+ sensor, calmodulin (CaM). We have recently found that protein kinase CK2 and protein phosphatase 2a (PP2a) associate with SK2 channels in brain. CK2 and PP2a, respectively, phosphorylate and de-phosphorylate SK2-associated CaM on T80. The overall goal for our proposal is to determine the physiological significance of CK2 and PP2a mediated SK2 modulation in hippocampal CA1 neurons. We hypothesize that the N- and C-termini of the channel form a binding framework for CK2, and that PP2a is bound to the C-terminus of SK2. Positive charges in the N-terminus activate CK2, while spatially proximal negative charges in the C-terminal domain, induced by phosphorylation, reduce kinase activity. This mechanism allows CK2 and PP2a to regulate SK2's inhibitory effects on NMDA receptor activation in hippocampal CA1 neurons. Structure-function studies combined with biochemical protein dissection and lentiviral transgene expression provide a powerful methodology to rigorously test our hypotheses.

描述（由申请人提供）：SK通道会影响神经元兴奋性，突触可塑性和记忆的获取。 SK通道仅通过细胞内Ca2+离子门控，Ca2+门控通过与原型CA2+传感器，钙调蛋白（CAM）的本构相互作用来赋予SK通道。我们最近发现，蛋白激酶CK2和蛋白质磷酸酶2a（PP2A）与大脑中的SK2通道相关。 CK2和PP2A分别在T80上磷酸化和磷酸化的SK2相关CAM。我们建议的总体目标是确定海马CA1神经元中CK2和PP2A介导的SK2调节的生理意义。我们假设该通道的N端和C端形成了CK2的结合框架，并且PP2A与SK2的C端结合。 N末端激活CK2的阳性电荷，而磷酸化引起的C末端负电荷在空间近端负电荷中降低了激酶活性。该机制使CK2和PP2A可以调节SK2对海马CA1神经元中NMDA受体激活的抑制作用。结构功能研究与生化蛋白质解剖和慢病毒转基因表达相结合，提供了一种有力的方法来严格检验我们的假设。