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Circ Res. 2006 Apr 28;98(8):1048-54. Epub 2006 Mar 23.

KCNQ1 assembly and function is blocked by long-QT syndrome mutations that disrupt interaction with calmodulin.

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1
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Abstract

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 Ca(2+)-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 Ca(2+)-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.

[Indexed for MEDLINE]

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