CaMKII Holoenzyme Mechanisms in Opposing Forms of Synaptic Plasticity

突触可塑性相反形式的 CaMKII 全酶机制

• 批准号: 10676017
• 负责人: K. Ulrich Bayer
• 金额: $ 47.94万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676017
• 关键词: Address; Affinity; Angelman Syndrome; Binding; Brain; Ca(2+)-Calmodulin Dependent Protein Kinase; Calmodulin; Cognition; Data; FASTK Gene; Feedback; Frequencies; Funding; Glutamate Receptor; Hippocampus; Holoenzymes; Impaired cognition; Impairment; In Vitro; Intellectual functioning disability; Kinetics; Learning; Left; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Mental Depression; Molecular Computations; N-Methylaspartate; NUP214 gene; Neurons; Output; Pathologic; Perception; Phosphorylation; Physical condensation; Prevention; Reaction; Regulation; Role; Schizophrenia; Signal Transduction; Speed; Structure; Synapses; Synaptic plasticity; Tail; Testing; Work; brain cell; calmodulin-dependent protein kinase II; dimer; information processing; monomer; preference; tool

Project Summary/Abstract Stimulation of hippocampal NMDA-type glutamate receptors (NMDARs) can induce long-term potentiation (LTP) or depression (LTD), two opposing forms of synaptic plasticity that are thought to be required for higher brain functions such as learning, memory and cognition. This proposal will focus on the molecular computation that mediates the decision between these two forms of plasticity. LTP has long been known to require the Ca2+/calmodulin(CaM)-dependent protein kinase II (CaMKII) and its autophosphorylation at T286 (pT286), which generates Ca2+-independent “autonomous” CaMKII activity (~20% of the maximal Ca2+/CaM-stimulated activity). In the first funding period of this proposal, we have shown that CaMKII and pT286 are additionally required for LTD. But how can pT286 CaMKII possibly mediate both of these two opposing forms of plasticity? We have started to address this question in the second funding period: LTP additionally requires CaMKII binding to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B, and two mechanisms suppressed this binding during LTD. By contrast, LTD instead requires a distinct additional autophosphorylation, the inhibitory pT305/306, which blocks Ca2+/CaM binding, limits further pT286, and also directly inhibits GluN2B binding. The three regulatory CaMKII mechanisms (pT286, pT305/306, and GluN2B binding) are all thought to require the CaMKII holoenzyme structure and all cross-regulate each other. In order to elucidate how this cross- regulation works to enable the LTP vs LTD decision by CaMKII, we will here determine the specific holoenzyme rules underlying each mechanism. In three related but independent aims, the project will determine the holoenzyme rules for CaMKII phosphorylation at T286, phosphorylation at T305/306, and GluN2B interaction. A fourth aim will test effects on neuronal functions, which are expected to differ for LTP versus LTD.

项目总结/摘要 刺激海马NMDA型谷氨酸受体（NMDARs）可诱导长时程增强 (LTP)或抑郁症（LTD），两种相反形式的突触可塑性，被认为是需要更高的 大脑功能，如学习，记忆和认知。这项建议将集中在分子计算 在这两种可塑性之间起中介作用。长期以来，LTP一直被认为需要 Ca 2 +/钙调素（CaM）依赖性蛋白激酶II（CaMK II）及其T286（pT 286）处的自磷酸化， 其产生Ca 2+非依赖性“自主”CaMKII活性（最大Ca 2 +/CaM刺激的约20%）。 活动）。在该提案的第一个资助期，我们已经证明CaMKII和pT 286是额外的， 但是pT 286 CaMKII如何可能介导这两种相反形式的可塑性呢？ 我们已经开始在第二个融资期解决这个问题：LTP还需要CaMKII 与NMDA型谷氨酸受体（NMDAR）亚基GluN 2B结合，两种机制抑制了 相反，LTD需要一个独特的额外的自磷酸化， 抑制性pT 305/306，其阻断Ca 2 +/CaM结合，进一步限制pT 286，并且还直接抑制GluN 2B 约束力三种调节CaMKII的机制（pT 286、pT 305/306和GluN 2B结合）都被认为是 需要CaMKII全酶结构，并且都相互交叉调节。为了解释这个十字架- 调节工作，使LTP与LTD的决定，由CaMKII，我们将在这里确定具体的全酶 每种机制下的规则。在三个相关但独立的目标中，该项目将确定 全酶规则CaMKII在T286磷酸化，在T305/306磷酸化，和GluN 2B相互作用。 第四个目标将测试对神经元功能的影响，预计LTP与LTD的影响有所不同。