Modulation of Calcium Signaling in Neurons

神经细胞使用钙离子将电信号转化为细胞内的生化变化。电活动增加细胞内钙离子。一旦进入细胞，钙就扮演着信使的角色，将信息传递到细胞内部的不同部分，在那里它会触发从基因表达到神经递质和激素释放的各种过程。只有在电刺激或某些病理过程中，细胞内的钙浓度才会升高。在正常情况下，细胞内的钙浓度通过一系列复杂的途径将钙泵出细胞外，从而保持很低的细胞内钙浓度。这项建议的目的是研究三个钙调节过程的调节。1)细胞内有专门的细胞器，负责吸收、储存和释放钙。我们将研究调节细胞表面电活动与细胞内钙释放之间的耦合的信号。2)另一个能够吸收钙的细胞内细胞器是线粒体，也就是细胞的动力源。使用最近开发的方法来测量线粒体内的钙，将确定影响线粒体钙摄取的因素。3)钙负荷最终通过嵌入细胞表面膜的泵从细胞中移除。这些泵有许多遗传变异。目前尚不清楚这些变体在功能上有何不同。将确定各个泵变体的功能特性，特别是它们对调制的敏感性。为了实现这些目标，将在培养皿中培养神经元，并使用研究人员开发的光学和电生理仪器对其进行单独研究。这项工作将增加我们对神经元如何在分子和细胞水平上处理信息的理解，并可能揭示药物的新靶点。

Nerve cells use calcium ions to convert electrical signals into biochemical changes within the cell. Electrical activity increases intracellular calcium. Once inside the cell, calcium acts as a messenger carrying information to various parts of the cell interior where it acts to trigger processes ranging from gene expression to the release of neurotransmitters and hormones. Only during electrical stimulation, or during certain pathologies, is the calcium concentration in the cell elevated. Under normal conditions the intracellular calcium concentration is kept very low by a complex series of pathways which pump calcium out of the cell. The objective of this proposal is to study the modulation of three calcium regulatory processes. 1) Within the cell are specialized organelles that take up, store and release calcium. The signals that regulate the coupling of electrical activity at the cell surface to the release of calcium from these internal stores will be studied. 2) Another intracellular organelle that can take up calcium is the mitochondrion, the cell's powerhouse. Using recently developed methods to measure calcium within the mitochondrion, factors that influence mitochondrial calcium uptake will be determined. 3) Calcium loads are ultimately removed from the cell by pumps embedded in the cell-surface membrane. There are many genetic varieties of these pumps. It is not known how these variants differ functionally. The functional characteristics of individual pump variants, particularly their sensitivity to modulation, will be determined. To achieve these goals neurons will be grown in culture (in a dish), and studied individually with optical and electrophysiological instrumentation developed by the investigator. This work will increase our understanding of how neurons process information at the molecular and cellular level, and may reveal new targets for drugs.