TY - JOUR
T1 - Accessory subunit KChIP2 modulates the cardiac L-type calcium current
AU - Thomsen, Morten B
AU - Wang, Chaojian
AU - Ozgen, Nazira
AU - Wang, Hong-Gang
AU - Rosen, Michael R
AU - Pitt, Geoffrey S
N1 - Keywords: Animals; Calcium; Calcium Channels, L-Type; Cell Membrane; Cells, Cultured; Ion Transport; Kv Channel-Interacting Proteins; Male; Membrane Potentials; Mice; Mice, Knockout; Muscle Proteins; Protein Structure, Tertiary; Shal Potassium Channels
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
U2 - 10.1161/CIRCRESAHA.109.196972
DO - 10.1161/CIRCRESAHA.109.196972
M3 - Journal article
C2 - 19461043
SN - 0009-7330
VL - 104
SP - 1382
EP - 1389
JO - Circulation Research
JF - Circulation Research
IS - 12
ER -