The Sialyltransferase, ST3Gal4, Modulates Ventricular Electrical Signaling

Abstract

Sialic acids impact voltage‐gated Na+ channel (Nav) and K+ channel (Kv) function, but little is understood about how the glycosylation machinery influences electrical signaling. Diseases of glycosylation often cause symptoms consistent with changes in excitability that include arrhythmias. The sialyltransferase, ST3Gal4, is uniformly expressed throughout cardiac chambers and developmental stages. An ST3Gal4 knockout strain was used to investigate the role of sialylation in the cardiac electrical remodeling often associated with diseases of glycosylation. Data indicate ST3Gal4 deletion significantly affects Nav gating with no change in maximum current density. Activation voltages of voltage‐dependent kinetic components of K+ currents (IK), Ito and IKslow, were depolarized, along with a reduction in peak IK density. The ST3Gal4−/− ventricular myocyte refractory period was reduced and action potential waveform alterations were observed. Consistently, ST3Gal4−/− left ventricular epicardium demonstrated a reduced refractory period and was more susceptible to arrhythmias as observed through isolated whole heart optical mapping studies. The data indicate that relatively minor perturbations in the glycome cause significant changes in cardiac electrical signaling, highlighting the role of glycosylation in cardiac function. Additionally, these studies underscore the possible contribution of reduced sialylation as a mediator for the often observed changes in electrical excitability associated with diseases of glycosylation.