STRUCTURAL BASES OF T-TYPE CALCIUM CHANNEL FUNCTION

说明(改编自申请人的说明)：T型钙通道有 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，如 心脏起搏和塑造神经元的爆发性行为。他们的表情 在某些病理情况下表达上调，如心肌梗死 肥大。这提示，T型钙通道可能参与了血管紧张素转换酶 疾病进程的进展，或可能是治疗的有价值的目标。 最近，已经发现了几种T型通道成孔亚基的异构体 克隆(α-1G、-1H和-1I)，为研究 这类通道的分子结构、生理学和药理学。在……里面 这项建议，申请人建议调查的结构基础 T型钙通道的门控和离子选择性/渗透。五个具体目标 用来检验两个一般假设：(1)陡峭的电压依赖性 T-型钙通道闭合状态失活的原因是激活 门控，以及(2)低电压和高电压之间的选择性差异 激活的钙通道以及钙和钠通道之间的一组焦点 这些通道家族之间的孔道残留物的差异。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.