Regulation of Neuronal Excitability by Extracellular Calcium

细胞外钙对神经元兴奋性的调节

基本信息

批准号：
8791347
负责人：
Dejian Ren
金额：
$ 35万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791347
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 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&apos s solution Role Second Messenger Systems Seizures Signal Pathway Signal Transduction Surface Synaptic Cleft Testing Ventral Tegmental Area density excitatory neuron extracellular genetic approach in vivo neuronal excitability novel protein activation receptor screening second messenger voltage

项目摘要

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.

描述（由申请人提供）：该提案的主要目标是基于我们最近的几个意外发现来了解细胞外钙如何调节神经元的基础兴奋性。在低钙血症和癫痫等病理生理条件下，大脑中细胞外钙的浓度会显着下降。在生理条件下，神经元密度高的大脑区域和突触间隙等微区域中的细胞外钙浓度也会发生变化。细胞外钙浓度的降低通常会兴奋神经元。与广泛研究的钙作为第二信使的细胞内作用相比，细胞外钙控制的分子机制知之甚少。我们提出细胞外钙调节兴奋性的主要机制是通过我们发现的 NALCN 阳离子通道。利用生化、电生理学和小鼠遗传学方法，我们将 1) 确定 NALCN 对几个脑区细胞外钙刺激神经元的相对贡献； 2) 明确钙敏感性蛋白质的结构要求； 3）揭示调节通道复合体的信号。这些研究的结果将帮助我们了解在瘫痪、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。