T-TYPE CA2+ CHANNELS AND ALDOSTERONE SECRETION

说明书（改编自申请人的摘要）：醛固酮是一种主要的 导致充血性心力衰竭的病理生理学。醛固酮 产生是Ca 2+依赖性的，低压激活（LVA）Ca 2+通道是 肾上腺醛固酮生成细胞中钙电流的主要载体 球状的然而，关于激素如何控制这种活动， LVA频道LVA钙通道三个成员的克隆 家族提供了定义所涉及的分子机制的可能性。的 开发针对这些通道的药物将提供一种新的治疗方法， 策略，以抑制生产的醛固酮在高血压和 充血性心力衰竭在小球蚴中，Ca/CaM依赖蛋白 激酶II活性增加_1H通道开放的频率， 负电压，血管紧张素II控制CaM激酶活性。模型 已经开发了基于CaMK II亚基的异源表达的系统 与_ H1，模仿天然调节的通道。分子生物学， 生物化学和电生理学将被用来测试假设， 醛固酮长期和短期调节的重要组成部分 AngII引起的分泌依赖于_ H1通道的活性。的 具体的目的是确定哪些CaMKII亚型能够刺激 LVA通道;以确定_ 1H通道上的哪些结构域对于 CaMKII调节其活性;并确定变化的重要性 LVA钙通道活性对醛固酮分泌的影响 AngII。

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.