STRUCTURAL BASES OF T-TYPE CALCIUM CHANNEL FUNCTION

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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.