Accessory subunit KChIP2 modulates the cardiac L-Type calcium current

Abstract

Complex modulation of voltage-gated Ca currents through the interplay among Ca channels and various Ca-binding proteins is increasingly being recognized. The K channel interacting protein 2 (KChIP2), originally identified as an auxiliary subunit for KV4.2 and a component of the transient outward K channel (Ito), is a Ca-binding protein whose regulatory functions do not appear restricted to KV4.2. Consequently, we hypothesized that KChIP2 is a direct regulator of the cardiac L-type Ca current (ICa,L). We found that ICa,L density from KChIP2 myocytes is reduced by 28% compared to ICa,L recorded from wild-type myocytes (P<0.05). This reduction in current density results from loss of a direct effect on the Ca channel current, as shown in a transfected cell line devoid of confounding cardiac ion currents. ICa,L regulation by KChIP2 was independent of Ca binding to KChIP2. Biochemical analysis suggested a direct interaction between KChIP2 and the CaV1.2 α1C subunit N terminus. We found that KChIP2 binds to the N-terminal inhibitory module of α1C and augments ICa,L current density without increasing CaV1.2 protein expression or trafficking to the plasma membrane. We propose a model in which KChIP2 impedes the N-terminal inhibitory module of CaV1.2, resulting in increased ICa,L. In the context of recent reports that KChIP2 modulates multiple KV and NaV currents, these results suggest that KChIP2 is a multimodal regulator of cardiac ionic currents. © 2009 American Heart Association, Inc.