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Circulation Research. 2006;98:1048-1054
Published online before print March 23, 2006, doi: 10.1161/01.RES.0000218863.44140.f2
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(Circulation Research. 2006;98:1048.)
© 2006 American Heart Association, Inc.

Cellular Biology

KCNQ1 Assembly and Function Is Blocked by Long-QT Syndrome Mutations That Disrupt Interaction With Calmodulin

Smita Ghosh, Deborah A. Nunziato, Geoffrey S. Pitt

From the Departments of Pharmacology (S.G., D.A.N., G.S.P.) and Medicine, Division of Cardiology (G.S.P.), College of Physicians and Surgeons of Columbia University, New York, NY.

Correspondence to Geoffrey Pitt, Department of Medicine, Division of Cardiology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, PH 7W 318, New York, NY 10032. E-mail gp2004{at}columbia.edu

Calmodulin (CaM) has been recognized as an obligate subunit for many ion channels in which its function has not been clearly established. Because channel subunits associate early during channel biosynthesis, CaM may provide a mechanism for Ca2+-dependent regulation of channel formation. Here we show that CaM is a constitutive component of KCNQ1 K+ channels, the most commonly mutated long-QT syndrome (LQTS) locus. CaM not only acts as a regulator of channel gating, relieving inactivation in a Ca2+-dependent manner, but it also contributes to control of channel assembly. Formation of functional tetramers requires CaM interaction with the KCNQ1 C-terminus. This CaM-regulated process is essential: LQTS mutants that disrupt CaM interaction prevent functional assembly of channels in a dominant-negative manner. These findings offer a new mechanism for LQTS defects and provide a basis for understanding novel ways that intracellular Ca2+ and CaM regulate ion channels.


Key Words: KCNQ1 • KvLQT1 • IKs • calmodulin • long-QT syndrome


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