In myocardial tissues, a variety of potassium (K+) channels with distinct time- and voltage -dependent properties and pharmacological sensitivities have been identified. This heterogeneity has a physiological significance in the myocardium in that the various K+ channels function to control resting membrane potentials, the waveforms of action potentials, refractoriness and automaticity, and these channels are important targets for the actions of a variety of neurotransmitters, neurohormones and exogenous drugs. Interestingly, the molecular cloning of cardiac K+ channel pore-forming (alpha) subunits and, more recently, accessory (beta) subunits has revealed even greater potential for generating K+ channels diversity than was expected based on the electrophysiology, and the relationship between these subunits and the functional K+ channels in cardia cells is poorly understood. Heterologous expression of the various Kv alpha subunits for example, reveals K+ channels with properties similar - but not identical to the voltage-gate K+ channels in cardiac myocytes. In addition, biochemical studies reveal that cardiac myocytes express more Kvalpha subunits than expected if it is assumed that functional voltage-gated K+ channels are homomultimers. Taken together, these observations suggest the interesting possibility that the detailed properties of functional voltage-gated myocardial K+ channels are controlled association with beta subunits and/or myocyte-specific post- translational modifications and/or that functional channels comprise the protein products of two or more Kv alpha subunit genes. The experiments outlined in this proposal will test these hypotheses.
The specific aims are focussed on defining the relationship between the various Kv alpha subunits expressed and the functional depolarization- activated K+ channels, ITO and IK, in rat ventricular myocytes, and at determining if there are accessory (beta) subunits that contribute to formation of functional ITO and IK channels. A combination of biochemical, immunological, molecular and electrophysiological techniques will be exploited to achieve these aims.
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