Expression of the sialyltransferase, ST3Gal4, impacts cardiac voltage-gated sodium channel activity, refractory period and ventricular conduction

The sequential glycosylation process typically ends with sialic acid residues added through trans-Golgi sialyltransferase activity. Individuals afflicted with congenital disorders of glycosylation often have reduced glycoprotein sialylation and present with multi-system symptoms including hypotonia, seizures, arrhythmia and cardiomyopathy. Cardiac voltage-gated Na+ channel (Na-v) activity can be influenced by sialic acids likely contributing to an external surface potential causing channels to gate at less depolarized voltages. Here, a possible pathophysiological role for reduced sialylation is investigated by questioning the impact of gene deletion of the uniformly expressed beta-galactoside alpha-2,3-sialyltransferase 4 (ST3Gal4) on cardiac Na-v activity, cellular refractory period and ventricular conduction. Whole-cell patch-clamp experiments showed that ventricular Na-v from ST3Gal4 deficient mice (ST3Gal4(-)/(-)) gated at more depolarized potentials, inactivated more slowly and recovered from fast inactivation more rapidly than WT controls. Current-clamp recordings indicated a 20% increase in time to action potential peak and a 30 ms decrease in ST3Gal4(-)/(-) myocyte refractory period, concurrent with increased Nay recovery rate. Na-v expression, distribution and maximal Na+ current levels were unaffected by ST3Gal4 expression, indicating that reduced sialylation does not impact Na-v surface expression and distribution. However, enzymatic desialylation suggested that ST3Gal4(-)/(-) ventricular Na-v are less sialylated. Consistent with the shortened myocyte refractory period, epicardial conduction experiments using optical mapping techniques demonstrated a 27% reduction in minimum ventricular refractory period and increased susceptibility to arrhythmias in ST3Gal4(-)/(-) ventricles. Thus, deletion of a single sialyltransferase significantly impacts ventricular myocyte electrical signaling. These studies offer insight into diseases of glycosylation that are often associated with pathological changes in excitability and highlight the importance of glycosylation in cardiac physiology. (C) 2013 Elsevier Ltd. All rights reserved.