Modulation of SK2 by protein kinase CK2 and PP2a

蛋白激酶 CK2 和 PP2a 对 SK2 的调节

基本信息

批准号：
7268724
负责人：
Duane M Allen
金额：
$ 2.28万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7268724
关键词：
Action Potentials Affinity Apamin Architecture Attenuated Binding Binding Proteins Binding Sites Biochemical Biological Assay Brain C-terminal Calcium-Activated Potassium Channel Calmodulin Charge Complement Complex Data Dendritic Spines Development Dissection EF Hand Motifs Feedback Fire - disasters Frequencies Genes Glutathione S-Transferase Goals Hippocampus (Brain)In Vitro Injection of therapeutic agent Ions Kinetics Knockout Mice Learning Lobe Measurement Measures Mediating Membrane Methodology Methods MgATP Mutagenesis Mutation N-Methyl-D-Aspartate Receptors Neurons Numbers Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Physiological Processes Preparation Protein phosphatase Proteins Range Receptor Activation Regulation Serine Slice Structure Synaptic plasticity Testing Tetanus Threonine Training Vertebral column Voltage-Gated Potassium Channel base casein kinase II in vivo memory acquisition mutant neuronal excitability research study response sensor transgene expression

项目摘要

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 通道影响神经元兴奋性、突触可塑性和记忆获取。 SK 通道仅由细胞内 Ca2+ 离子门控，而 Ca2+ 门控是通过与原型 Ca2+ 传感器钙调蛋白 (CaM) 的组成型相互作用赋予 SK 通道的。我们最近发现蛋白激酶CK2和蛋白磷酸酶2a（PP2a）与大脑中的SK2通道相关。 CK2 和 PP2a 分别在 T80 上磷酸化和去磷酸化 SK2 相关的 CaM。我们提案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。我们假设通道的 N 端和 C 端形成 CK2 的结合框架，并且 PP2a 与 SK2 的 C 端结合。 N 端的正电荷激活 CK2，而 C 端结构域中的空间邻近负电荷由磷酸化诱导，降低激酶活性。这种机制使得 CK2 和 PP2a 能够调节 SK2 对海马 CA1 神经元 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，为严格检验我们的假设提供了强有力的方法。