Activation of the Voltage-Gated Potassium Channel by Amphiphilic Glycopeptides

Voltage-gated ion channels (VGICs) are allosterically modulated by glycosaminoglycan proteoglycans and sialic acid glycans. However, the structural diversity and heterogeneity of these biomolecules pose significant challenges to precisely delineate their underlying structure-activity relationships. Herein, we demonstrate how heparan sulfate (HS) and sialic acid synthetic glycans appended on amphiphilic glycopeptide backbone influence cell membrane persistence and modulate the gating of the Kv2.1 channel. Utilizing a panel of amphiphilic glycopeptides comprising HS disaccharides and sialic acid trisaccharide glycans, we observed that sulfation of HS and flexible alpha(2-6) sialylation result in prolonged persistence of glycopeptides on the cell membrane compared to non-sulfated HS and alpha(2-3) sialylation respective. This variation in glycocalyx composition was associated with a noticeable difference in the effects of these compounds on the activation and deactivation properties of the voltage-gated Kv2.1 channel with our strongest membrane associating compound demonstrating the most potent channel-activation propensity. Our findings demonstrate that sulfation charges on glycopeptide play a critical role in their membrane association propensities and endow them with VGIC activation properties. These results provide a valuable insight into the role of cell surface glycans in VGIC activities.