STRUCTURAL BASES OF T-TYPE CALCIUM CHANNEL FUNCTION

描述（改编自申请人的描述）：T型Ca通道是 存在于多种细胞类型（心肌细胞、平滑肌细胞 和神经元），并参与各种生理功能， 心脏的起搏和神经元的爆发行为。它们的表达 在某些病理条件下，如心肌 肥厚这表明T型钙通道可能参与了细胞内钙离子的代谢。 疾病过程的进展，或者可能是有价值的治疗靶点。 最近，T型通道成孔亚基的几种亚型已被发现。 克隆（alpha-1G，-1H和-1I），提供了研究 分子结构、生理学和药理学这类通道。在 在该建议中，申请人建议调查 T型Ca通道的门控和离子选择性/渗透。五个具体目标 提出测试两个一般假设：（1）陡峭的电压依赖性 T型钙通道关闭状态的失活来自激活 门控，以及（2）低电压和高电压之间的选择性差异 激活的Ca通道以及Ca和Na通道之间的通道产生于 这些通道家族之间孔残基的差异。这些实验 将使用电生理学、诱变和分子建模技术。

DESCRIPTION (adapted from the applicant's description): T-type Ca channels are present in a wide variety of cell types (cardiac myocytes, smooth muscle cells and neurons), and participate in various physiological functions such as pacemaking in heart and shaping bursting behavior in neurons. Their expression is upregulated under certain pathological conditions such as myocardial hypertrophy. This suggests that the T-type Ca channels may be involved in the progression of disease processes, or may be a valuable target of therapies. Recently, several isoforms of T-type channel pore-forming subunits have been cloned (alpha-1G, -1H, and -1I), providing an opportunity to study the molecular structure, physiology and pharmacology of this class of channels. In this proposal, the applicant proposes to investigate the structural basis of gating and ion selectivity/permeation of T-type Ca channels. Five specific aims are proposed to test two general hypotheses: (1) the steep voltage-dependence of inactivation from closed states of T-type Ca channels arises from activation gating, and (2) differences in selectivity between low- and high-voltage activated Ca channels and between Ca and Na channels arise from a focal set of differences in pore residues between these channel families. These experiments will use techniques of electrophysiology, mutagenesis and molecular modeling.