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(Circulation Research. 2009;104:1382.)
© 2009 American Heart Association, Inc.

Cellular Biology

Accessory Subunit KChIP2 Modulates the Cardiac L-Type Calcium Current

Morten B. Thomsen, Chaojian Wang, Nazira Özgen, Hong-Gang Wang, Michael R. Rosen, Geoffrey S. Pitt

From the Departments of Pharmacology (M.B.T., M.R.R.) and Pediatrics (N.O., M.R.R.), College of Physicians and Surgeons, Columbia University, New York; and Ion Channel Research Unit, Department of Medicine (C.W., H.-G.W., G.S.P.), Duke University Medical Center, Durham, NC. Present address for M.B.T.: Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Denmark.

Correspondence to Dr Geoffrey S. Pitt, Department of Medicine, Duke University Medical Center, Box 103030 Medical Center, Durham, NC 27710. E-mail geoffrey.pitt{at}duke.edu

Complex modulation of voltage-gated Ca²⁺ currents through the interplay among Ca²⁺ channels and various Ca²⁺-binding proteins is increasingly being recognized. The K⁺ channel interacting protein 2 (KChIP2), originally identified as an auxiliary subunit for K_V4.2 and a component of the transient outward K⁺ channel (I_to), is a Ca²⁺-binding protein whose regulatory functions do not appear restricted to K_V4.2. Consequently, we hypothesized that KChIP2 is a direct regulator of the cardiac L-type Ca²⁺ current (I_Ca,L). We found that I_Ca,L density from KChIP2^–/– myocytes is reduced by 28% compared to I_Ca,L recorded from wild-type myocytes (P<0.05). This reduction in current density results from loss of a direct effect on the Ca²⁺ channel current, as shown in a transfected cell line devoid of confounding cardiac ion currents. I_Ca,L regulation by KChIP2 was independent of Ca²⁺ binding to KChIP2. Biochemical analysis suggested a direct interaction between KChIP2 and the Ca_V1.2 _1C subunit N terminus. We found that KChIP2 binds to the N-terminal inhibitory module of _1C and augments I_Ca,L current density without increasing Ca_V1.2 protein expression or trafficking to the plasma membrane. We propose a model in which KChIP2 impedes the N-terminal inhibitory module of Ca_V1.2, resulting in increased I_Ca,L. In the context of recent reports that KChIP2 modulates multiple K_V and Na_V currents, these results suggest that KChIP2 is a multimodal regulator of cardiac ionic currents.

Key Words: ion channels • mouse models • amino terminal inhibitory module • auxiliary subunit • Ca_V1.2