Regulation of Neuronal Excitability by Extracellular Calcium

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之上，以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，脑内细胞外钙浓度可显著下降。在生理条件下，高神经元密度脑区和突触间隙等微域的细胞外钙浓度也会发生变化。细胞外钙浓度的降低通常使神经元兴奋。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。利用生物化学、电生理学和小鼠遗传学方法，我们将1)确定NALCN对大脑几个区域细胞外钙激发神经元的相对贡献；2)明确蛋白质对钙敏感性的结构要求；3)揭示调节通道复合体的信号。这些研究的结果将有助于我们了解在麻痹、癫痫和癫痫等生理和病理生理条件下，体钙如何在分子水平上调节神经元的兴奋性。

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.