Calmodulin is essential for cardiac IKS channel gating and assembly: Impaired function in long-QT mutations

Liora Shamgar, Lijuan Ma, Nicole Schmitt, Yoni Haitin, Asher Peretz, Reuven Wiener, Joel Hirsch, Olaf Pongs, Bernard Attali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

171 Scopus citations

Abstract

The slow IKS K+ channel plays a major role in repolarizing the cardiac action potential and consists of the assembly of KCNQ1 and KCNE1 subunits. Mutations in either KCNQ1 or KCNE1 genes produce the long-QT syndrome, a life-threatening ventricular arrhythmia. Here, we show that long-QT mutations located in the KCNQ1 C terminus impair calmodulin (CaM) binding, which affects both channel gating and assembly. The mutations produce a voltage-dependent macroscopic inactivation and dramatically alter channel assembly. KCNE1 forms a ternary complex with wild-type KCNQ1 and Ca 2+-CaM that prevents inactivation, facilitates channel assembly, and mediates a Ca2+-sensitive increase of IKS-current, with a considerable Ca2+-dependent left-shift of the voltage-dependence of activation. Coexpression of KCNQ1 or IKS channels with a Ca 2+-insensitive CaM mutant markedly suppresses the currents and produces a right shift in the voltage-dependence of channel activation. KCNE1 association to KCNQ1 long-QT mutants significantly improves mutant channel expression and prevents macroscopic inactivation. However, the marked right shift in channel activation and the subsequent decrease in current amplitude cannot restore normal levels of IKS channel activity. Our data indicate that in healthy individuals, CaM binding to KCNQ1 is essential for correct channel folding and assembly and for conferring Ca2+- sensitive IKS-current stimulation, which increases the cardiac repolarization reserve and hence prevents the risk of ventricular arrhythmias.

Original languageAmerican English
Pages (from-to)1055-1063
Number of pages9
JournalCirculation Research
Volume98
Issue number8
DOIs
StatePublished - Apr 2006
Externally publishedYes

Bibliographical note

Funding Information:
This work was partially funded by FCT, Portugal, through projects CERN/S/FIS/1048/98, PBICT/C/CTM/1891/95 and grants under the PRAXIS XXI Program (J.P.A.), and ITN (J.G.C.).

Keywords

  • Calmodulin
  • KCNE
  • KCNQ
  • Kv7
  • Long QT
  • Potassium channels

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