Kv7.1 isoform gradients in the heart: New potential approach to alter repolarization reserve

Abstract

Potassium channels have important roles in cardiac electrophysiology. In particular, the voltage-gated Kþ channel mediating the slow delayed rectifying current (IKs) is central during ventricular repolarization in humans. Long-QT syndrome type 1 is characterized by a reduction in IKs. 1 The channel complex is composed of 4 Kv7.1 protein subunits that form a pore which is regulated by KCNE subunits that substantially change the biophysical properties of the channel. For a brief account on the correct nomenclature of genes and proteins governing IKs, see Lundby et al. 3 Pharmacological, acquired, or congenital loss of IKs confer action-potential prolongation, T-wave abnormalities, augmented spatial and temporal repolarization heterogeneities, increased risk of early afterdepolarizations, triggered activity, and torsades de pointes arrhythmias. Beta-adrenergic stimulation during the fight-or-flight response augments IKs, counteracting the increased depolarizing force induced by the larger calcium current and safeguarding against excessive prolongation of the action potentials during elevated heart rates. Serines 27 and 92 are phosphorylated in Kv7.1 after stimulation of the adrenergic β1 receptor causing channel activation at lower membrane potentials and larger current density. Repolarization reserve has been defined as the ability of the heart to remain in normal rhythm despite challenges on repolarization, and IKs is critical to limiting action potential prolongation due to its sympathetic modulation. Hence, when heart rate increases with adrenergic stimulation, the ability of the action potential to shorten lies in part with IKs and a reduced current will delay repolarization, setting the stage for ventricular arrhythmias. In the human heart, Kv7.1 exists in 2 isoforms derived from alternative splicing from the same gene, KCNQ1. Isoform 1 is the full-length channel pore subunit, whereas isoform 2 is an N-terminal truncated splicing variant