Role of the Calcium-Independent Transient Outward Current I to1 in Shaping Action Potential Morphology and Duration

Abstract

Abstract —The Kv4.3-encoded current ( I Kv4.3 ) has been identified as the major component of the voltage-dependent Ca 2+ -independent transient outward current ( I to1 ) in human and canine ventricular cells. Experimental evidence supports a correlation between I to1 density and prominence of the phase 1 notch; however, the role of I to1 in modulating action potential duration (APD) remains unclear. To help resolve this role, Markov state models of the human and canine Kv4.3- and Kv1.4-encoded currents at 35°C are developed on the basis of experimental measurements. A model of canine I to1 is formulated as the combination of these Kv4.3 and Kv1.4 currents and is incorporated into an existing canine ventricular myocyte model. Simulations demonstrate strong coupling between L-type Ca 2+ current and I Kv4.3 and predict a bimodal relationship between I Kv4.3 density and APD whereby perturbations in I Kv4.3 density may produce either prolongation or shortening of APD, depending on baseline I to1 current level.