Targeted Deletion of KCNE4 Impairs Ventricular Repolarization in Mice

With 1000 people succumbing to sudden cardiac death each day in the United States alone, it is imperative to continue to elucidate the molecular basis for cardiac ion channel function and dysfunction. KCNE4 (MiRP3) is a 1TM K+ channel β subunit, inherited variants in which are associated with atrial fibrillation (AF) and Long QT Syndrome, a disorder linked to defective ventricular myocyte repolarization. The mechanisms of pathology are unclear. Here, we deleted the Kcne4 gene in mice and assessed the effects on cardiac function. Transcriptomic analysis suggested no global gene remodeling and hemodynamic parameters were normal. Electrocardiographic measurements revealed normal cardiovascular electrical function at 5 months, but genotype-specific QTc prolongation at 18 months of age. Consistent with this finding, using patch clamp analysis of cardiac myocyte currents we discovered that older Kcne4-/- mice exhibit diminished K+ current in septal ventricular myocytes compared to that of age- and sex-matched Kcne4+/+ littermates. Kinetic and pharmacological analyses pinpointed the affected current to be the 50 µM 4-aminopyridine (4-AP)-sensitive component of the IK,slow current, which is conducted in mouse ventricles by the Kv1.5 delayed rectifier α subunit. We also found that in CHO cells, KCNE4 co-expression increases the sensitivity of KV1.5 to block by 4-AP. Consistent with these two latter findings, Kcne4-/- mice were less susceptible to 4-AP-induced QTc prolongation (i.e., beyond their existing QTc prolongation) compared to age- and sex-matched Kcne4+/+ littermates. We conclude that Kcne4 regulates Kv1.5 in vivo in mouse heart and that disruption of this regulation is a primary basis for ventricular repolarization defects in Kcne4-/- mice. In human heart, Kv1.5 expression is restricted to the atrial myocytes; future studies should also be aimed at elucidating a potential atrial role for Kv1.5-KCNE4 complexes.