CaMKII in neuronal signaling and degeneration

CaMKII 在神经元信号传导和变性中的作用

• 批准号: 8542908
• 负责人: Andy Hudmon
• 金额: $ 32.92万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542908
• 关键词: Acute; Acute Disease; Affinity; Astrocytes; Biochemical; Brain; Brain region; Calcium; Calcium Signaling; Calcium/calmodulin-dependent protein kinase; Cells; Cessation of life; Chronic; Communication; Complex; Data; Development; Diffuse; Diffusion; Disease; Enzymes; Epilepsy; Frequencies; Functional disorder; Glutamates; Goals; Hippocampus (Brain); Holoenzymes; In Vitro; Ischemia; Kinetics; Learning; Life; Light; Mediating; Membrane; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neurotransmitters; Particulate; Phosphorylation; Physiological; Play; Predisposition; Process; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Publishing; Role; Signal Pathway; Signal Transduction; Solutions; Stimulus; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Traumatic Brain Injury; Work; calmodulin-dependent protein kinase II; density; enzyme substrate; excitotoxicity; flexibility; innovation; insight; neuron apoptosis; neuronal survival; neurotransmission; new therapeutic target; novel; oxidation; prevent; protein aggregation; research study

DESCRIPTION (provided by applicant): Calcium signaling plays a central yet surprisingly flexible role in the function of neurons, contributing to neurotransmission, synaptic plasticity, ad neuronal death. Calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII) is a multifunctional Ser/Thr protein kinase that is essential for normal hippocampal synaptic plasticity and spatial learning in mice. CaMKII is believed to decode the frequency of calcium transients (i.e. neuronal activity) in to graded levels of activity. Unlike the role of CaMKII in physiologica calcium signaling, its role in pathological calcium signaling is largely unknown. Aberrant calcium signaling accompanies multiple disease states associated with glutamate, the major excitatory neurotransmitter in the brain. Excessive glutamate release accompanies acute disease states (e.g. ischemia and brain trauma) as well as chronic neurodegenerative disorders (delayed neuronal death with ischemia and epilepsy). Exactly what CaMKII is doing in excitotoxicity is unknown; however, there are clues worth noting. First, CaMKII is highly expressed (1-2% of total protein) in regions of the brain highly susceptible to excitotoxicity. Second, ischemic duration correlates to CaMKII inactivation and neuronal death. Third, preventing CaMKII from activating during excitotoxicity prevents neuronal death; a process that also prevents CaMKII from undergoing activity-dependent inactivation and aggregation. Fourth, we have recently published that inhibiting CaMKII directly induces neuronal apoptosis via calcium dysregulation and hyperexcitability to aberrant glutamate signaling. In this application, we propose to understand novel mechanisms underlying CaMKII substrate phosphorylation, inactivation and aggregation in both highly controlled biochemical experiments and in living cells. In addition, we propose to determine if CaMKII inactivation in astrocytes disrupts normal glial-neuronal communication; a process our preliminary data indicates leads to astrocyte degeneration. These experiments will not only advance our understanding of CaMKII signaling during pathological calcium signaling, but they will also shed new light on basic mechanisms related to CaMKII structure, substrate phosphorylation, and protein aggregation. Conclusions from these studies may also identify novel therapeutic targets and mechanisms to disrupt neuronal and glia death induced by glutamate excitotoxicity.

描述（由申请人提供）：钙信号传导在神经元功能中发挥着核心但令人惊讶的灵活作用，有助于神经传递、突触可塑性和神经元死亡。钙调蛋白 (CaM) 依赖性蛋白激酶 II (CaMKII) 是一种多功能 Ser/Thr 蛋白激酶，对于正常海马突触可塑性至关重要 和小鼠的空间学习。 CaMKII 被认为可以将钙瞬变（即神经元活动）的频率解码为活动的分级水平。与 CaMKII 在生理钙信号传导中的作用不同，其在病理钙信号传导中的作用很大程度上未知。异常的钙信号传导伴随着与谷氨酸（大脑中主要的兴奋性神经递质）相关的多种疾病状态。过量的谷氨酸释放伴随着急性疾病状态（例如缺血和脑外伤）以及慢性神经退行性疾病（缺血和癫痫引起的迟发性神经元死亡）。 CaMKII 在兴奋性毒性中的确切作用尚不清楚；然而，有一些线索值得注意。首先，CaMKII 在对兴奋性毒性高度敏感的大脑区域高度表达（占总蛋白的 1-2%）。其次，缺血持续时间与 CaMKII 失活和神经元死亡相关。第三，防止 CaMKII 在兴奋性毒性期间激活可防止神经元死亡；这一过程还可以防止 CaMKII 发生活性依赖性失活和聚集。第四，我们最近发表了抑制 CaMKII 通过钙失调和异常谷氨酸信号传导过度兴奋直接诱导神经元凋亡。在此应用中，我们建议了解高度控制的生化实验和活细胞中 CaMKII 底物磷酸化、失活和聚集的新机制。此外，我们建议确定星形胶质细胞中 CaMKII 失活是否会破坏正常的胶质神经元通讯；我们的初步数据表明这一过程会导致星形胶质细胞变性。这些实验不仅将增进我们对病理性钙信号传导过程中 CaMKII 信号传导的理解，而且还将为与 CaMKII 结构、底物磷酸化和蛋白质聚集相关的基本机制提供新的线索。这些研究的结论还可能确定新的治疗靶点和机制，以破坏谷氨酸兴奋性毒性引起的神经元和神经胶质细胞死亡。