Voltage-dependent potassium channels (K+ channels) play a key role in the proper function of excitable tissues such as in the nervous system and the heart. In cardiac tissue, a variety of K+ channels fine tune the electrical events that lead to the modulation of the heartbeat. Research conducted under this proposal will yield information on the structural properties and biophysical characteristics of the various types of cardiac K+ channels. This will allow integration of the current contributed by an individual K+ channels to the total ionic current in different cardiac cell types. To achieve this, we will determine the structural diversity of human heart K+ channels by cloning cardiac cDNAs and their function by expression in Xenopus oocytes. A biophysical and pharmacological profile of both homotetrameric and, with coexpression, possible heterotetrameric K+ channel formation will be established. This will be followed by an examination of the spatial distribution and the relative abundance of the individual K+ channel subunits throughout the human heart using the polymerase chain reaction (PCR_ technique in combination with in situ hybridization and immunohistochemistry. To evaluate a role for K+ channels in cardiac pathologies, similar tests will be performed with diseased tissues. Such a functional characterization in combination with studies on channel distribution will serve as the basis to correlate the 'isolated' ionic currents detected with the 'pure' cloned channels with their physiological counterparts in cardiac tissues. A comparative molecular and electrophysiological description of cardiac K+ channels in normal and diseased tissues should lead to a better understanding of the electrical events underlying the heartbeat in normal and diseased states.
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