Abstract 235: A Micropeptide Regulator of Voltage-gated Potassium Channels Controls Cardiac Rhythm

Voltage-gated potassium (K + ) channels (VGKCs) are essential regulators of the cardiac action potential and are required to maintain normal heart rhythm and contractility. Voltage-dependent activation, conductance and membrane trafficking of K + channels are tightly controlled by a family of single transmembrane regulatory cofactors (KCNE1-5), which co-assemble with pore forming K + channels in cell membranes. Human mutations in voltage-gated K + channels and their regulatory subunits are associated with Long QT syndrome (LQTS), a condition in which the repolarization of the heart is delayed and can lead to arrhythmias, syncope and sudden death. Here we identify a cardiac-enriched transmembrane micropeptide encoded by a small open reading frame, which we named KCNEmini, due to its sequence and structural homology with members of the KCNE family of VGKC regulators. We show that KCNEmini directly binds to and co-localizes with VGKCs in the plasma membrane and functions as a novel regulator of K + channel kinetics. Disruption of KCNEmini in mice resulted in QT interval prolongation and cardiac dysfunction. These studies shed light on a previously unrecognized regulator of K + handling in the heart, which may be an important future therapeutic target for the early diagnosis and treatment of human lethal cardiac arrhythmias.