A Molecular Mechanism for Adrenergic-Induced Long QT Syndrome

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 ( I Ks ) 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 I Ks , shifted the current-voltage I-V relation of I Ks to more positive potentials, and accelerated the I Ks deactivation rates in a concentration-dependent manner. In addition, the coexpression of G269S and WT blunted the activation of I Ks in response to isoproterenol or PKA stimulation. Lastly, a phosphomimetic substitution in G269S did not show an increased I Ks . Conclusions G269S modestly affected I Ks in control conditions, but it almost completely blunted I Ks 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.