Sialytransferase ST3Gal4 Deficient Mice Demonstrate Left Ventricular Action Potential Extension and Attenuated IK

Abstract

Extracellular protein glycosylation is a ubiquitous cellular process that is vital to normal physiology. Aberrant glycosylation of both genetic and acquired etiologies are observed in severe disease states including congenital disorders of glycosylation and Chagas disease, which afflict millions. Cardiomyopathies including altered electrical signaling are a hallmark of these glycosylation disorders; although, little of the underlying mechanisms are understood. Cardiac conduction and contraction is dependent on various types of voltage-sensitive ion channels that are extensively modified by protein glycosylation. Our lab and others have demonstrated an isoform-specific role of glycosylation in channel gating. Protein glycosylation is a sequential process that involves hundreds of genes that are regulated throughout development and our lab showed that regulated glycosylation alters cardiac electrical signaling. One such glycogene, ST3 beta-galactoside alpha-2,3-sialyltransferase 4 (ST3Gal4), adds negatively charged sialic acids to many membrane proteins including voltage gated ion channels that likely contribute to the extracellular surface charge. Myocytes isolated from the left ventricular apex of ST3Gal4 deficient mice (n=5) demonstrated a 30 % (p<0.05) increase in the APD90 compared to gender and age matched controls (n=8). The current densities of both the peak and the slowly inactivating sustained (IKslow) repolarizing voltage-sensitive potassium currents were attenuated (n<0.05) at all depolarizing potentials in the ST3Gal4 mice (n=6) compared to controls (n=13). This reduction in potassium current should act to extend the action potential, as observed. The fact that the absence of a single gene involved in protein glycosylation can lead to such deleterious effects on cardiac electrical signaling may provide insight into other diseases of glycosylation that affect millions world-wide.