KCNQ1 assembly and function is blocked by long-QT syndrome mutations that disrupt interaction with calmodulin.
Journal Article (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 28, 2006
Published In
Volume / Issue
- 98 / 8
Start / End Page
- 1048 - 1054
PubMed ID
- 16556866
Electronic International Standard Serial Number (EISSN)
- 1524-4571
Digital Object Identifier (DOI)
- 10.1161/01.RES.0000218863.44140.f2
Language
- eng
Conference Location
- United States