Multiple types of voltage-gated K+ (Kv) channels with distinct time- and voltage dependent properties and pharmacological sensitivities have been identified in the mammalian myocardium. This diversity has a physiological significance in that the various Kv channels play distinct roles in controlling action potential waveforms and refractoriness, and they are differentially modulated by endogenous and exogenous drugs and in the damaged or diseased heart. The cloning of Kv channel pore-forming (alpha) and accessory (minK/ MiRPs, Kv beta, KChAPs, and KChIPs) subunits has revealed even greater potential for generating K+ channel diversity than was expected, and there is considerable interest in defining the relationships between these subunits and functional myocardial Kv channels, as well as in exploring the molecular mechanisms involved in the regulation and modulation of these channels. The studies proposed here exploit genetic strategies to identify the molecular correlates of the voltage-gated K+ currents, Ito,f, IK,slow and Iss in (adult) mouse ventricular myocytes. Experiments in aim #1 will test the hypothesis that heteromeric assembly of Kv4 alpha subunits underlies mouse ventricular Ito,f. The experiments in aims #2 and #3 will define the molecular correlates of IK,slow and Iss, and test the hypothesis that Kv2 alpha subunits do not assemble in vivo, but rather form two distinct populations of IK.slow channels.
In aims #4 and #5, we propose to explore directly the role(s) of the accessory KChTP2 and Kv beta1 subunits in the generation of voltage-gated K+ channels, particularly Ito,f, in mouse ventricular myocytes. We anticipate that these studies will provide new and fundamentally important insights into the molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium.
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