Regulation of Kv4.3 current by KChIP2 splice variants: A component of native cardiac I_to?

Background - The transient outward potassium current (I_to) encoded by the Kv4 family of potassium channels is important in the repolarization of cardiac myocytes. KChIPs are a recently identified group of Ca²⁺-binding accessory subunits that modulate Kv4-encoded currents. KChIP2 is the only family member expressed in the heart. Methods and Results - We previously cloned 2 novel splice variants of KChIP2 from human heart, named KChIP2S and KChIP2T. The transmural distribution of KChIP2 mRNA and protein in human and canine left ventricle was examined using kinetic RT-PCR and Western blots in the same tissues. A steep gradient of mRNA with greater KChIP2 expression in the epicardium was observed. However, no gradient of immunoreactive protein was observed. Immunocytochemistry reveals KChIP2 expression in the t-tubules and the nucleus. The predominant effects of all 3 KChIP2 splice variants on hKv4.3-encoded current are to increase the density, slow the current decay in a Ca²⁺-dependent manner, and hasten recovery from inactivation in a splice variant-specific fashion. Conclusions - A family of KChIP2 proteins is expressed in human hearts that exhibits differential modulation of hKv4.3 current in a Ca²⁺-dependent fashion. The effect of KChIP2 on the biophysical properties of expressed Kv4.3 current and the absence of a gradient of protein across the ventricular wall suggest that KChIP2 is either not a requisite component of human or canine ventricular I_to or that its functional effect is being affected or additionally modified by other factors present in myocardial cells.