Role of the calcium-independent transient outward current I(to1) in shaping action potential morphology and duration

The Kv4.3-encoded current (I(Kv4.3)) has been identified as the major component of the voltage-dependent Ca²⁺-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 Ca²⁺ 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.