Accessory subunit KChIP2 modulates the cardiac L-type calcium current.
Complex modulation of voltage-gated Ca2+ currents through the interplay among Ca2+ channels and various Ca(2+)-binding proteins is increasingly being recognized. The K+ channel interacting protein 2 (KChIP2), originally identified as an auxiliary subunit for K(V)4.2 and a component of the transient outward K+ channel (I(to)), is a Ca(2+)-binding protein whose regulatory functions do not appear restricted to K(V)4.2. 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(V)1.2 alpha(1C) subunit N terminus. We found that KChIP2 binds to the N-terminal inhibitory module of alpha(1C) and augments I(Ca,L) current density without increasing Ca(V)1.2 protein expression or trafficking to the plasma membrane. We propose a model in which KChIP2 impedes the N-terminal inhibitory module of Ca(V)1.2, 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.
Thomsen
Morten B
MB
Department of Medicine, Duke University Medical Center, Box 103030 Medical Center, Durham, NC 27710, USA.
Wang
Chaojian
C
Ozgen
Nazira
N
Wang
Hong-Gang
HG
Rosen
Michael R
MR
Pitt
Geoffrey S
GS
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017136:Ion Transport / Q000502:physiology; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins; D009124:Muscle Proteins; D051672:Shal Potassium Channels; D002118:Calcium