Regulation of Neuronal Excitability by Extracellular Calcium

细胞外钙对神经元兴奋性的调节

• 批准号: 8217080
• 负责人: Dejian Ren
• 金额: $ 35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8217080
• 关键词: Affinity; Amino Acids; Biochemical; Brain; Brain region; Calcium; Calcium-Sensing Receptors; Calmodulin; Cations; Cells; Charge; Complex; Coupling; Data; Drops; Electrophysiology (science); Epilepsy; G Protein-Coupled Receptor Genes; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Goals; Health; Heart; Hippocampus (Brain); Hypocalcemia result; Image; Inhibitory Concentration 50; Knock-out; Knockout Mice; Mediating; Membrane; Molecular; Mus; Mutant Strains Mice; Nervous system structure; Neurons; Paralysed; Phosphatidylinositol 4,5-Diphosphate; Physiological; Proteins; Regulation; Relative (related person); Ringer' s solution; Role; Screening procedure; Second Messenger Systems; Seizures; Signal Pathway; Signal Transduction; Surface; Synaptic Cleft; Testing; Ventral Tegmental Area; density; excitatory neuron; extracellular; in vivo; neuronal excitability; novel; protein activation; receptor; second messenger; voltage

DESCRIPTION (provided by applicant): The major goal of this proposal is to build on our several recent unexpected findings to understand how extracellular calcium regulates the basal excitability of neurons. Under pathophysiological conditions such as hypocalcemia and epilepsy, concentration of extracellular calcium can drop significantly in the brain. Extracellular calcium concentration can also change under physiological conditions in brain regions with high neuronal density and in microdomains such as the synaptic cleft. A decrease in extracellular calcium concentration usually excites neurons. The molecular mechanisms underlying the control by extracellular calcium are poorly understood, in contrast with the extensively investigated intracellular roles of calcium as a second messenger. We propose that a major mechanism by which extracellular calcium regulates excitability is through the NALCN cation channel we discovered. Using biochemical, electrophysiology and mouse genetics approaches, we will 1) determine the relative contribution of NALCN to the neuronal excitation by extracellular calcium in several brain regions; 2) define the structural requirements of the protein in the calcium sensitivity; and 3) uncover the signals that regulate the channel complex. Results from these studies will help us understand how body calcium regulates neuronal excitability at the molecular level under physiological and pathophysiological conditions such as paralysis, seizure and epilepsy. PUBLIC HEALTH RELEVANCE: This proposal studies how extracellular calcium controls the excitability of the nervous system. Results from these studies will help understand neuronal excitabilities in physiological and pathophysiological conditions such as paralysis, seizure and epilepsy

描述（由申请人提供）：本提案的主要目标是建立在我们最近的几个意想不到的发现，以了解细胞外钙如何调节神经元的基础兴奋性。在病理生理条件下，如低钙血症和癫痫，细胞外钙的浓度可以显着下降的大脑。细胞外钙浓度也可以在生理条件下在具有高神经元密度的脑区域和在微域如突触间隙中改变。细胞外钙离子浓度的降低通常使神经元兴奋。细胞外钙离子控制的分子机制知之甚少，与广泛研究的细胞内钙离子作为第二信使的作用相反。我们认为细胞外钙调节兴奋性的一个主要机制是通过我们发现的NALCN阳离子通道。利用生物化学、电生理学和小鼠遗传学方法，我们将1）确定NALCN对几个脑区域中细胞外钙对神经元兴奋的相对贡献; 2）定义钙敏感性中蛋白质的结构要求; 3）揭示调节通道复合物的信号。这些研究的结果将有助于我们了解在瘫痪、癫痫发作和癫痫等生理和病理生理条件下，体内钙如何在分子水平上调节神经元兴奋性。 公共卫生相关性：该提案研究细胞外钙如何控制神经系统的兴奋性。这些研究的结果将有助于了解神经元的兴奋性在生理和病理生理条件下，如瘫痪，癫痫发作和癫痫