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: 8438856
• 负责人: Andy Hudmon
• 金额: $ 34.11万
• 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/8438856
• 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; 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. PUBLIC HEALTH RELEVANCE: CaMKII is serine/threonine protein kinase that undergoes aggregation and inactivation following excitotoxic calcium signaling associated with ischemia and epilepsy. The long-term goal of these studies is to identify molecular mechanisms and therapeutic strategies to disrupt CaMKII's vulnerability to excitotoxic glutamate-signaling; a process we also believe will reveal novel insights into synaptic plasticity and the function of CaMKII in physiological calcium signaling.

描述（由申请人提供）：钙信号在神经元的功能中起着中心但出奇的灵活作用，有助于神经传递，突触可塑性，AD神经元死亡。钙 - 钙调蛋白（CAM）依赖性蛋白激酶II（CAMKII）是一种多功能的Ser/Thr蛋白激酶，对正常海马突触可塑性至关重要 和小鼠的空间学习。据信CAMKII将钙瞬变（即神经元活性）的频率解码为分级的活性水平。与CAMKII在Physiologica钙信号传导中的作用不同，其在病理钙信号中的作用在很大程度上尚不清楚。异常的钙信号传导伴随着与谷氨酸相关的多种疾病状态，谷氨酸是大脑中主要的兴奋性神经递质。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（缺血和癫痫病延迟神经元死亡）伴随着谷氨酸过多的释放（例如缺血和脑创伤）。 Camkii在兴奋性毒性中所做的事情尚不清楚。但是，有一些线索值得注意。首先，在高度容易受到兴奋性毒性的大脑区域中，CAMKII高度表达（占总蛋白质的1-2％）。其次，缺血性持续时间与CaMKII失活和神经元死亡有关。第三，防止CAMKII在兴奋性期间激活会阻止神经元死亡。这一过程也可以阻止CAMKII受到活动依赖性失活和聚集的过程。第四，我们最近发表了抑制CAMKII直接通过钙失调和过度兴奋的谷氨酸信号传导直接诱导神经元凋亡。在此应用中，我们建议理解CAMKII底物磷酸化，灭活和聚集的新机制，在高度控制的生化实验和活细胞中。此外，我们建议确定CAMKII在星形胶质细胞中的失活是否会破坏正常的神经神经神经元通信。我们的初步数据表明的过程导致星形胶质变性。这些实验不仅会提高我们对病理钙信号过程中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有关的基本机制提供新的启示。这些研究的结论还可以确定新的治疗靶标和机制，以破坏谷氨酸兴奋性毒性诱导的神经元和神经胶质死亡。 公共卫生相关性：CAMKII是丝氨酸/苏氨酸蛋白激酶，在与缺血和癫痫相关的兴奋性钙信号传导后经历聚集和失活。这些研究的长期目标是确定分子机制和治疗策略，以破坏Camkii脆弱性抗激毒性谷氨酸信号的脆弱性；我们还认为，一个过程将揭示有关突触可塑性和CAMKII在生理钙信号传导中的功能的新见解。