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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Ghosh, S; Nunziato, DA; Pitt, GS

Published Date

  • April 2006

Published In

Volume / Issue

  • 98 / 8

Start / End Page

  • 1048 - 1054

PubMed ID

  • 16556866

Pubmed Central ID

  • 16556866

Electronic International Standard Serial Number (EISSN)

  • 1524-4571

International Standard Serial Number (ISSN)

  • 0009-7330

Digital Object Identifier (DOI)

  • 10.1161/01.res.0000218863.44140.f2

Language

  • eng