OAT--A NOVEL CARDIAC POTASSIUM CHANNEL WITH 2 P DOMAINS

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Potassium channels catalyze the permeation of K/+ ions across cell membranes. In this way, they mediate function of excitable tissues such as cardiac muscle. Until 1995, the defining attribute of all recognized K/+ channel subunits was the presence of a single pore-forming P domain. In 1995, we cloned from the budding yeast Saccharomyces cerevisiae the first member of a new superfamily of K+ channels that carry 2 P domains within on continuous polypeptide./1 In 1996, we isolated an example of a second lineage of 2 P domain K/+ channels from Drosophila melanogaster./2 Our studies of these two channels revealed phenotypes that were previously unrecognized among cloned channels and showed the new superfamily to be distinctive in both structure and function. Now, we have isolated 2 P domain K/+ channel genes from mouse and human. In this project, we propose first to study murine OAT, a cardiac-specific, pH-sensitive, 2 P domain K/+ channel and, subsequently, its human homolog. Our long-term goals are three-fold: to explore the structural basis for OAT channel function, to identify the determinants of OAT gene expression, and, to elucidate the role of OAT channels in cardiac development and physiology. Our six aims are: (1) to characterize the function and pharmacology of murine OAT channels; (2) to study the membrane topology and subunit stoichiometry of OAT channels; (3) to characterize cellular modulation of murine OAT channels; (4) to determine the expression pattern, native composition and role of OAT channels in vivo (and, thereby, to determine if OAT is the molecular correlate of cardiac current called Ik/p); (5) to identify cis- actin sequences and trans-actin factors that regulate the murine OAT gene; and, (6) to assess how salient attributes of murine OAT are recapitulated in humans. Cardiac physiology is intimately tied to K/+ channel function. It follows the basic aspects of ion channel function in developing and mature heart must be understood if cardiac disorders are to be diagnosed, treated and cured. Our motivation is the knowledge that OAT channels are expressed at high levels in developing and nature heart. Because identification of the superfamily and its cardiac variant is recent, basic understanding of their role in health and disease lies ahead. We now have the tools to achieve this understanding.