ATP-SENSITIVE POTASSIUM CHANNELS IN THE HEART

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In the heart, a major sensor of the metabolic state, and hence a potentially major player in ischemia, is the ATP-sensitive potassium (KATP) channel, which links metabolic state to electrical excitability. This project seeks to understand the molecular basis for metabolic control of KATP channels in the heart, and the pathophysiological role of these channels in the response to ischemia. Previously it has been shown that sulfonylurea receptor (SUR) isoforms, and in particular the nucleotide binding folds (NBFs) are critical determinants of tissue-specific KATP function. It has also been shown that SUR1 and SUR2A differentially regulate KATP channels, with SUR1 generating more active channels under physiological conditions. Novel transgenic mice overexpressing KATP channels subunits in the heart were developed, including mice overexpressing SUR1 and SUR2A. Overexpression of SUR1 only caused sudden death. In order to extend these preliminary data experiments are proposed to address the following question: (1) How do NBF-nucleotide interactions regulate KATP channels? In order to achieve this aim, a series of novel tools have been developed, including fluorescent reporter constructs of SUR1 and a novel specific anti-SUR1 antibody. These will be used in a series of experiments aimed at a biochemical and recombinant protein level approach to the problem. The results of the proposed experiments will bring detailed insight to the structural and mechanistic basis of KATP channel function and the role of differential SUR isoforms in cardiac function.