T-TYPE CA2+ CHANNELS AND ALDOSTERONE SECRETION

描述(摘自申请者的摘要)：醛固酮是一种 对充血性心力衰竭的病理生理学有贡献。醛固酮 产生依赖于钙离子，低电压激活(LVA)的钙离子通道 肾上腺醛固酮产生细胞钙电流的主要载体 肾小球。然而，人们对荷尔蒙如何控制这种活动知之甚少。 LVA频道。LVA钙通道三个成员的最新克隆 家族提供了定义相关分子机制的可能性。这个 针对这些通道的药物的开发将提供一种新的治疗方法 抑制高血压和高血压患者的醛固酮产生的策略 充血性心力衰竭在球状带中，钙/钙调素依赖性蛋白 KinaseII活性增加_1H通道的开放频率 负电压，而血管紧张素II控制钙调蛋白激酶的活性。一位模特 基于CaMKII亚基异源表达的系统已被开发 WITH_H1，模拟通道的本机调节。分子生物学， 生物化学和电生理学将被用来检验这一假设 醛固酮长期和短期调节的重要组成部分 血管紧张素Ⅱ诱导的分泌依赖于_H1通道的活性。这个 具体目的是确定哪些CaMKII亚型能够刺激 LVA通道；确定_1H通道上的哪些区域对 CaMKII对其活动的调节；并确定变化的重要性 LVA钙通道活性对醛固酮分泌的刺激作用 安吉。

DESCRIPTION (Adapted from the Applicant's Abstract): Aldosterone is a major contributor to the pathophysiology of congestive heart failure. Aldosterone production is Ca2+ dependent and low-voltage activated (LVA) Ca2+ channels are major carriers of Ca current in the aldosterone-producing cells of the adrenal glomerulosa. However, little is known about how hormones control the activity of LVA channels. The recent cloning of three members of the LVA Ca2+ channel family offers the possibility to define the molecular mechanisms involved. The development of drugs that target these channels will provide a new therapeutic strategy to suppress the production of aldosterone in hypertension and congestive heart failure. In the zona glomerulosa, Ca/CaM-dependent protein kinaseII activity increases the frequency of opening of _1H channels at negative voltages, and angiotensin II controls CaMkinase activity. A model system has been developed based on heterologous expression of a CaMKII subunit with _ H1 that mimics the native regulation of the channel. Molecular biology, biochemistry and electrophysiology will be used to test the hypothesis that important components of both long- and short-term regulation of aldosterone secretion elicited by AngII depend on the activity of the _ H1 channels. The specific aims are to determine which CaMKII isoforms are capable of stimulating LVA channels; to determine which domains on _ 1H channels are important for CaMKII regulation of its activity; and to determine then importance of changes in LVA Ca2+ channel activity on the secretion of aldosterone stimulated by AngII.