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(Circulation Research. 2006;98:1055.)
© 2006 American Heart Association, Inc.

Cellular Biology

Calmodulin Is Essential for Cardiac I_KS Channel Gating and Assembly

Impaired Function in Long-QT Mutations

Liora Shamgar, Lijuan Ma, Nicole Schmitt, Yoni Haitin, Asher Peretz, Reuven Wiener, Joel Hirsch, Olaf Pongs, Bernard Attali

From the Department of Physiology & Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (L.S., Y.H., A.P., B.A.); Institut für Neurale Signalverarbeitung, ZMNH, Hamburg, Germany (L.M., N.S., O.P.); Department of Biochemistry, Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel (R.W., J.H.); and Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark (N.S.)

Correspondence to Bernard Attali, PhD, Department of Physiology & Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. E-mail battali{at}post.tau.ac.il

The slow I_KS K⁺ channel plays a major role in repolarizing the cardiac action potential and consists of the assembly of KCNQ1 and KCNE1 subunits. Mutations in either KCNQ1 or KCNE1 genes produce the long-QT syndrome, a life-threatening ventricular arrhythmia. Here, we show that long-QT mutations located in the KCNQ1 C terminus impair calmodulin (CaM) binding, which affects both channel gating and assembly. The mutations produce a voltage-dependent macroscopic inactivation and dramatically alter channel assembly. KCNE1 forms a ternary complex with wild-type KCNQ1 and Ca²⁺-CaM that prevents inactivation, facilitates channel assembly, and mediates a Ca²⁺-sensitive increase of I_KS-current, with a considerable Ca²⁺-dependent left-shift of the voltage-dependence of activation. Coexpression of KCNQ1 or I_KS channels with a Ca²⁺-insensitive CaM mutant markedly suppresses the currents and produces a right shift in the voltage-dependence of channel activation. KCNE1 association to KCNQ1 long-QT mutants significantly improves mutant channel expression and prevents macroscopic inactivation. However, the marked right shift in channel activation and the subsequent decrease in current amplitude cannot restore normal levels of I_KS channel activity. Our data indicate that in healthy individuals, CaM binding to KCNQ1 is essential for correct channel folding and assembly and for conferring Ca²⁺-sensitive I_KS-current stimulation, which increases the cardiac repolarization reserve and hence prevents the risk of ventricular arrhythmias.

Key Words: KCNQ • potassium channels • Kv7 • calmodulin • KCNE • long QT

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