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

KCNQ1 Assembly and Function Is Blocked by Long-QT Syndrome Mutations That Disrupt Interaction... KCNQ1 Assembly and Function Is Blocked by Long-QT Syndrome Mutations That Disrupt Interaction With Calmodulin Smita Ghosh, Deborah A. Nunziato, Geoffrey S. Pitt 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 -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 -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 Ca and CaM regulate ion channels. (Circ Res. 2006;98:1048-1054.) Key Words: KCNQ1 K LQT1 I calmodulin long-QT syndrome v Ks he long-QT syndrome (LQTS) is a collection of inherited previous reports showing that I isaCa -responsive cur- http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Circulation Research Wolters Kluwer Health

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

Pitt, Geoffrey S.
Circulation Research , Volume 98 (8) – Apr 1, 2006
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References (53)

ISSN
0009-7330
eISSN
1524-4571
DOI
10.1161/01.RES.0000218863.44140.f2
pmid
16556866
Publisher site
See Article on Publisher Site

Abstract

KCNQ1 Assembly and Function Is Blocked by Long-QT Syndrome Mutations That Disrupt Interaction With Calmodulin Smita Ghosh, Deborah A. Nunziato, Geoffrey S. Pitt 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 -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 -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 Ca and CaM regulate ion channels. (Circ Res. 2006;98:1048-1054.) Key Words: KCNQ1 K LQT1 I calmodulin long-QT syndrome v Ks he long-QT syndrome (LQTS) is a collection of inherited previous reports showing that I isaCa -responsive cur-

Journal

Circulation Research – Wolters Kluwer Health

Published: Apr 1, 2006

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