Role of the calcium-independent transient outward current Ito1 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 degreesC 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.