Differential expression of voltage-gated ion channel isoforms and variation in the number of a single channel isoform are two mechanisms by which the cardiac action potential can be regulated. Voltage-gated K+ channels represent the most complex group of ion channels in the heart and play a central role in cardiac membrane repolarization during the action potential. The research outlined in this application will focus on the regulation of voltage-sensitive potassium channels present in mammalian heart. Seven distinct K+ channels have already been cloned by this laboratory from rat and human heart. In order to correlate these cloned channels with native myocyte currents, immunohistochemistry will be performed on tissue sections with antibodies that currently exist and antisera under production. In addition, identification of the K+ channel isoforms expressed in a recently available atrial cell line will correlate K+ channel structure with atrial K+ currents. Whether these isoforms assemble into heterotetramers in the intact heart or in the atrial cell line will be determined. No information exists on the mechanisms by which a cell maintains the proper number of cell surface K+ channels. Therefore, the cellular regulatory mechanisms responsible for maintaining the physiologically correct number of cell surface K+ channels will be examined using a tissue culture expression system. Following determination of the regulatory role of 5' and 3' untranslated sequence, the basic parameters of channel biosynthesis and intracellular transport the will be examined using pulse-chase techniques and antibody based affinity-purification. The role that the C-terminal amino acids play in biosynthesis, subunit assembly and intracellular targeting will also be examined. Since the voltage-gated potassium channels expressed in the heart are found in many excitable tissues, this research will have significant impact outside the field of cardiac potassium channel physiology.
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