RGS14 Regulation of CaM/CaMKII Signaling in Hippocampal CA2 Synaptic Plasticity

RGS14 对海马 CA2 突触可塑性中 CaM/CaMKII 信号传导的调节

• 批准号: 8649860
• 负责人: Paul Robert Evans
• 金额: $ 4.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2016-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649860
• 关键词: Adenylate Cyclase; Affect; Alzheimer' s Disease; Area; Autistic Disorder; Behavior; Binding; Biochemical; Bioluminescence; Bipolar Disorder; Calcium; Calcium Binding; Calcium Signaling; Calcium/calmodulin-dependent protein kinase; Calmodulin; Cell physiology; Cells; Co-Immunoprecipitations; Cognition; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Dendrites; Dendritic Spines; Disease; Ectopic Expression; Energy Transfer; Epilepsy; Episodic memory; Event; Exhibits; GTP-Binding Protein Regulators; GTP-Binding Proteins; Glutamates; Guanosine Triphosphate; HRAS gene; Hippocampus (Brain); Human; In Vitro; Ischemia; Learning; Life; Link; Long-Term Potentiation; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MEKs; Mass Spectrum Analysis; Memory; Messenger RNA; Molecular; Mus; Mutate; Mutation; Neurons; Pathway interactions; Phosphorylation; Phosphorylation Site; Physiological; Property; Proteins; Protocols documentation; RGS Proteins; Regulation; Relative (related person); Role; Schizophrenia; Signal Pathway; Signal Transduction; Signaling Protein; Slice; Synapses; Synaptic plasticity; Testing; Viral; Work; base; calmodulin-dependent protein kinase II; cell growth regulation; dentate gyrus; gain of function; hippocampal pyramidal neuron; human disease; inhibitor/antagonist; insight; loss of function; mutant; nervous system disorder; novel; novel therapeutics; postsynaptic; public health relevance; ras Guanine Nucleotide Exchange Factors; scaffold; sensor; transmission process

DESCRIPTION (provided by applicant): Synaptic plasticity within the hippocampus is highly correlated with encoding episodic memories and cognition in humans, and this ability of neurons to strengthen/weaken synaptic inputs has been well studied at CA3-CA1 synapses. Inputs from CA3 Schaffer collaterals form synapses on proximal dendrites of both CA2 and CA1 pyramidal neurons, but CA2 neurons resist long-term potentiation (LTP), the strengthening of synaptic connections, following protocols that produce LTP in CA1 neurons. The molecular mechanisms regulating plasticity in CA2 neurons and the role of area CA2 in overall hippocampal function and behavior are not known. Regulator of G Protein Signaling 14 (RGS14) is a signaling protein that is highly enriched in the dendrites and spines of CA2 pyramidal neurons that is a natural suppressor of LTP. Mice lacking RGS14 mRNA/protein (RGS14-KO) display a robust and nascent capacity for LTP in CA2, with no effect on plasticity in area CA1. RGS14-KO mice also have enhanced hippocampal-dependent learning and memory relative to wild- type littermates. Taken together, these data show that RGS14 is a natural suppressor of CA2 synaptic plasticity and learning and memory. However, the mechanism(s) by which RGS14 limits LTP in area CA2 are not understood. RGS14 is a complex scaffold/effector that integrates G protein and H-Ras/MAPK signaling pathways to suppress ERK signaling. Consistently, application of a MEK inhibitor blocks the nascent LTP observed in area CA2 of RGS14-KO mice. Previous work had suggested robust calcium handling and extrusion underlie the lack of plasticity observed in area CA2, but until very recently, no defined connection between RGS14 and calcium signaling relevant to plasticity. New data shows that RGS14 interacts with the key intracellular calcium sensor calmodulin (CaM) in a calcium-dependent manner. Postsynaptic calcium entry is required for typical activity- dependent plasticity induction. Following calcium influx, calcium binds CaM (Ca2+/CaM) to initiate several downstream signaling cascades required for LTP induction. Specifically, CaM activates CaM-dependent protein kinase II (CaMKII) and PKA. New evidences shows RGS14 is phosphorylated by CaMKII as well. Based on these findings, my working hypothesis is that CaM binding to and CaMKII phosphorylation of RGS14 alter its known functions, and RGS14 interacts with known calcium-activated pathways to suppress LTP in area CA2. I will test this hypothesis in the following specific aims. In aim 1, I will test how CaM binding and CaMKII phosphorylation modulate RGS14 activiy. In aim 2, I will determine how RGS14 interactions with CaM and CaMKII impact LTP induction in area CA2.

描述（由申请人提供）： 海马内的突触可塑性与人类的编码情景记忆和认知高度相关，并且神经元加强/减弱突触输入的这种能力已经在CA 3-CA 1突触中得到了很好的研究。来自CA 3 Schaffer侧支的输入在CA 2和CA 1锥体神经元的近端树突上形成突触，但是CA 2神经元抵抗长时程增强（LTP），即突触连接的加强，遵循在CA 1神经元中产生LTP的协议。调节CA 2神经元可塑性的分子机制以及CA 2区在整个海马功能和行为中的作用尚不清楚。G蛋白信号调节因子14（Regulator of G Protein Signaling 14，RGS 14）是一种在CA 2锥体神经元的树突和棘中高度富集的信号蛋白，是LTP的天然抑制因子。缺乏RGS 14 mRNA/蛋白的小鼠（RGS 14-KO）在CA 2中显示出强大的新生LTP能力，对CA 1区的可塑性没有影响。相对于野生型同窝出生的小鼠，RGS 14-KO小鼠还具有增强的海马依赖性学习和记忆。总之，这些数据表明RGS 14是CA 2突触可塑性和学习记忆的天然抑制剂。然而，RGS 14限制区域CA 2中的LTP的机制尚不清楚。 RGS 14是一个复杂的支架/效应器，其整合G蛋白和H-Ras/MAPK信号通路以抑制ERK信号传导。因此，MEK抑制剂的应用阻断了在RGS 14-KO小鼠的CA 2区中观察到的新生LTP。以前的工作表明，在CA 2区观察到的缺乏可塑性的基础是强大的钙处理和挤出，但直到最近，RGS 14和与可塑性相关的钙信号之间没有明确的联系。新的数据表明，RGS 14与关键的细胞内钙传感器钙调素（CaM）以钙依赖性方式相互作用。突触后钙离子进入是典型的活动依赖性可塑性诱导所必需的.在钙离子内流后，钙离子结合CaM（Ca 2 +/CaM）以启动LTP诱导所需的几个下游信号级联。具体地，CaM激活CaM依赖性蛋白激酶II（CaMKII）和PKA。新的证据表明RGS 14也被CaMK II磷酸化。 基于这些发现，我的工作假设是，钙调素结合和钙调素激酶II磷酸化的RGS 14改变其已知的功能，和RGS 14与已知的钙激活途径相互作用，以抑制LTP在CA 2区。我将在以下具体目标中检验这一假设。在目标1中，我将测试CaM结合和CaMK II磷酸化如何调节RGS 14活性。在目标2中，我将确定RGS 14与CaM和CaMKII的相互作用如何影响CA 2区的LTP诱导。