The sialic acid component of the β1 subunit modulates voltage-gated sodium channel function

Voltage-gated sodium channels (Na-v) are responsible for initiation and propagation of nerve, skeletal muscle, and cardiac action potentials. Na-v are composed of a pore-forming alpha subunit and often one to several modulating beta subunits. Previous work showed that terminal sialic acid residues attached to alpha subunits affect channel gating. Here we show that the fully sialylated beta(1) subunit induces a uniform, hyperpolarizing shift in steady state and kinetic gating of the cardiac and two neuronal alpha subunit isoforms. Under conditions of reduced sialylation, the beta(1)-induced gating effect was eliminated. Consistent with this, mutation of beta(1) N-glycosylation sites abolished all effects of beta(1) on channel gating. Data also suggest an interaction between the cis effect of alpha sialic acids and the trans effect of beta(1) sialic acids on channel gating. Thus, beta(1) sialic acids had no effect on the gating of the heavily glycosylated skeletal muscle alpha subunit. However, when glycosylation of the skeletal muscle alpha subunit was reduced through chimeragenesis such that alpha sialic acids did not impact gating, beta(1) sialic acids caused a significant hyperpolarizing shift in channel gating. Together, the data indicate that beta(1) N-linked sialic acids can modulate Na-v gating through an apparent saturating electrostatic mechanism. A model is proposed in which a spectrum of differentially sialylated Na-v can directly modulate channel gating, thereby impacting cardiac, skeletal muscle, and neuronal excitability.