Objectives: This study sought to explore molecular mechanisms underlying the adrenergic-induced QT prolongation associated with KCNQ1 mutations. Background: The most frequent type of congenital long QT syndrome is LQT1, which is caused by mutations in the gene (KCNQ1) that encodes the alpha subunit of the slow component of delayed rectifier K+ current (IKs) channel. We identified 11 patients from 4 unrelated families that are heterozygous for KCNQ1-G269S. Most patients remained asymptomatic, and their resting corrected QT intervals ranged from normal to borderline but were prolonged significantly during exercise. Methods: Wild-type (WT) KCNQ1 and/or KCNQ1-G269S (G269S) were expressed in mammalian cells with KCNE1. I Ks-like currents were measured in control conditions or after isoproterenol or protein kinase A (PKA) stimulation using the patch-clamp technique. Additionally, experiments that incorporated the phosphomimetic KCNQ1 substitution, S27D, in WT or KCNQ1-G269S were also performed. Results: The coexpression of WT-KCNQ1 with varying amounts of G269S decreased IKs, shifted the current-voltage I-V relation of IKs to more positive potentials, and accelerated the IKs deactivation rates in a concentration-dependent manner. In addition, the coexpression of G269S and WT blunted the activation of IKs in response to isoproterenol or PKA stimulation. Lastly, a phosphomimetic substitution in G269S did not show an increased IKs. Conclusions: G269S modestly affected IKs in control conditions, but it almost completely blunted IKs responsiveness in conditions that simulate or mimic PKA phosphorylation of KCNQ1. This insensitivity to PKA stimulation may explain why patients with G269S mutation showed an excessive prolongation of QT intervals on exercise.
|Number of pages||9|
|Journal||Journal of the American College of Cardiology|
|State||Published - Mar 4 2014|
Bibliographical noteFunding Information:
This work was supported by research grants from the Ministry of Education, Culture, Science, and Technology of Japan (to Dr. Horie); Health Science Research Grants from the Ministry of Health, Labor and Welfare of Japan for Clinical Research on Measures for Intractable Diseases (to Dr. Horie); Translational Research Funds from Japan Circulation Society (to Dr. Horie); and National Natural Science Foundation of China ( #81273501 to Drs. Wu and Ding). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Wu and Naiki contributed equally to this paper.
- KCNQ1 mutation
- heterologous expression
- long QT syndrome
- protein kinase A stimulation
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine