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(Circulation Research. 2005;96:730.)
© 2005 American Heart Association, Inc.

Cellular Biology

Impaired KCNQ1–KCNE1 and Phosphatidylinositol-4,5-Bisphosphate Interaction Underlies the Long QT Syndrome

Kyu-Ho Park, Julien Piron, Shehrazade Dahimene, Jean Mérot, Isabelle Baró, Denis Escande, Gildas Loussouarn

From the L’Institut du Thorax, INSERM U533, Faculté de Médecine, Nantes, France. Kyu-Ho Park’s present address is UMR7099, Institut de Biologie Physico-Chimique, 75005 Paris, France.

Reprint requests to Gildas Loussouarn, L’Institut du Thorax, INSERM U533, Faculté de Médecine, 1 rue Gaston Veil, BP 53508, 44035 Nantes, France. E-mail gildas.loussouarn{at}nantes.inserm.fr

Nearly a hundred different KCNQ1 mutations have been reported as leading to the cardiac long QT syndrome, characterized by prolonged QT interval, syncopes, and sudden death. We have previously shown that phosphatidylinositol-4,5-bisphosphate (PIP₂) regulates the KCNQ1–KCNE1 complex. In the present study, we show that PIP₂ affinity is reduced in three KCNQ1 mutant channels (R243H, R539W, and R555C) associated with the long QT syndrome. In giant excised patches, direct application of PIP₂ on the cytoplasmic face of the three mutant channels counterbalances the loss of function. Reintroduction of a positive charge by application of methanethiosulfonate ethylammonium on the cytoplasmic face of R555C mutant channels also restores channel activity. The channel affinity for a soluble analog of PIP₂ is decreased in the three mutant channels. By using a model that describes the KCNQ1–KCNE1 channel behavior and by fitting the relationship between the kinetics of deactivation and the current amplitude obtained in whole-cell experiments, we estimated the PIP₂ binding and dissociation rates on wild-type and mutant channels. The dissociation rate of the three mutants was higher than for the wild-type channel, suggesting a decreased affinity for PIP₂. PIP₂ binding was magnesium-dependent, and the PIP₂-dependent equilibrium constant in the absence of magnesium was higher with the wild-type than with the mutant channels. Altogether, our data suggest that a reduced PIP₂ affinity of KCNQ1 mutants can lead to the long QT syndrome.

Key Words: KCNQ1 • KCNE1 • phosphatidylinositol-4,5-bisphosphate • long QT syndrome

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