In-Silico Modeling of the Functional Role of Reduced Sialylation in Sodium and Potassium Channel Gating of Mouse Ventricular Myocytes

Cardiac ion channels are highly glycosylated membrane proteins with up to 30% of the protein's mass containing glycans. Heart diseases often accompany individuals with congenital disorders of glycosylation (CDG). However, cardiac dysfunction among CDG patients is not yet fully understood. There is an urgent need to study how aberrant glycosylation impacts cardiac electrical signaling. Our previous works reported that congenitally reduced sialylation achieved through deletion of the sialyltransferase gene, ST3Gal4, leads to altered gating of voltage-gated Na + and K + channels (Na v and K v , respectively). However, linking the impact of reduced sialylation on ion channel gating to the action potential (AP) is difficult without performing computer experiments. Also, decomposing the sum of K+ currents is difficult because of complex structures and components of K v channels (e.g., K v 4.2, and K v 1.5). In this study, we developed in-silico models to describe the functional role of reduced sialylation in both Na v and K v gating and the AP using in vitro experimental data. Modeling results showed that reduced sialylation changes K v gating as follows: 1) The steady-state activation voltages of K v isoforms are shifted to a more depolarized potential. 2) Aberrant K + currents (IKslow and Ito) contribute to a prolonged AP duration, and altered Na + current (INa) contributes to a shortened AP refractory period. This study contributes to a better understanding of the functional role of reduced sialylation in cardiac dysfunction that shows strong potential to provide new pharmaceutical targets for the treatment of CDG-related heart diseases.