Isoproterenol Exacerbates a Long QT Phenotype in Kcnq1-Deficient Neonatal Mice: Possible Roles for Human-Like Kcnq1 Isoform 1 and Slow Delayed Rectifier K⁺ Current

Abstract

To determine whether the neonatal mouse can serve as a useful model for studying the molecular pharmacological basis of Long QT Syndrome Type 1 (LQT1), which has been linked to mutations in the human KCNQ1 gene, we measured QT intervals from electrocardiogram (ECG) recordings of wild-type (WT) and Kcnq1 knockout (KO) neonates before and after injection with the ␤-adrenergic receptor agonist, isoproterenol (0.17 mg/ kg, i.p.). Modest but significant increases in JT, QT, and ratecorrected QT (QTc) intervals were found in KO neonates relative to WT siblings during baseline ECG assessments (QTc ϭ 57 Ϯ 3 ms, n ϭ 22 versus 49 Ϯ 2 ms, n ϭ 28, respectively, p Ͻ 0.05). Moreover, JT, QT, and QTc intervals significantly increased following isoproterenol challenge in the KO (p Ͻ 0.01) but not the WT group (p ϭ 0.57). Furthermore, whole-cell patch-clamp recordings show that the slow delayed rectifier K ϩ current (I Ks ) was absent in KO but present in WT myocytes, where it was strongly enhanced by isoproterenol. This finding was confirmed by showing that the selective I Ks inhibitor, L-735,821, blocked I Ks and prolonged action potential duration in WT but not KO hearts. These data demonstrate that disruption of the Kcnq1 gene leads to loss of I Ks , resulting in a long QT phenotype that is exacerbated by ␤-adrenergic stimulation. This phenotype closely reflects that observed in human LQT1 patients, suggesting that the neonatal mouse serves as a valid model for this condition. This idea is further supported by new RNA data showing that there is a high degree of homology (Ͼ88% amino acid identity) between the predominant human and mouse cardiac Kcnq1 isoforms.

SUMOylation determines the voltage required to activate cardiac I Ks channels

“…1B) (19,20,(27)(28)(29). nCM expressing a scrambled shRNA and eGFP expressed from a lentivirus retained parameters for I Ks like those in wild-type cells.…”

IKr and IKs remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits

“…The combination of pharmacological I Ks blockade and ␤-adrenergic stimulation prolongs the action potential in canine cardiac Purkinje cells (6) and enhances arrhythmogenicity in arterially perfused canine left ventricular wedge preparations (1). Repolarization abnormalities reminiscent of long QT syndrome were exacerbated by isoproterenol administration in a mouse knockout model lacking the Kcnq1 gene that encodes the pore-forming protein underlying I Ks (9,26).…”

Regulation of Voltage Gated K+ Channel KCNE1/KCNQ1 by the Janus Kinase JAK3

“…KCNQ1 knockout mice suffer from deafness [46,47], impairment of gastric acid secretion [47,48], and deranged intestinal electrolyte and substrate transport [33]. KCNQ1 deficiency further impairs cardiac repolarization [49]. In humans, genetic defects of the K + channel subunits KCNE1 or KCNQ1 lead to hearing loss and cardiac arrhythmia [28,29,50].…”