Title : Isoform-specific effects of the
beta2 subunit on
voltage-gated sodium channel gating
Abstract :
- Voltage-gated sodium channels ( Nav ) are complex glycoproteins comprised of an alpha subunit and often one to several beta subunits
- We have shown that sialic acid residues linked to Nav alpha and beta1 subunits alter channel gating
- To determine whether beta2-linked sialic acids similarly impact Nav gating, we co-expressed beta2 with Nav1 .5 or Nav1 .2 in Pro5 (complete sialylation) and in Lec2 (essentially no sialylation) cells
- Beta2 sialic acids caused a significant hyperpolarizing shift in Nav1 .5 voltage-dependent gating, thus describing for the first time an effect of beta2 on Nav1 .5 gating
- In contrast, beta2 caused a sialic acid-independent depolarizing shift in Nav1 .2 gating
- A deglycosylated mutant, beta(2-DeltaN), had no effect on Nav1 .5 gating, indicating further the impact of beta2 N-linked sialic acids on Nav1 .5 gating
- Conversely, beta(2-DeltaN) modulated Nav1 .2 gating virtually identically to beta2 , confirming that beta2 N-linked sugars have no impact on Nav1 .2 gating
- Thus, beta2 modulates Nav gating through multiple mechanisms possibly determined by the associated alpha subunit
- Beta1 and beta2 were expressed together with Nav1 .5 or Nav1 .2 in Pro5 and Lec2 cells
- Together beta1 and beta2 produced a significantly larger sialic acid-dependent hyperpolarizing shift in Nav1 .5 gating
- Under fully sialylating conditions, the Nav1 .2
- beta1. beta2 complex behaved like Nav1 .2 alone
- When sialylation was reduced, only the sialic acid-independent depolarizing effects of beta2 on Nav1 .2 gating were apparent
- Thus, the varied effects of beta1 and beta2 on Nav1 .5 and Nav1 .2 gating are apparently synergistic and highlight the complex manner, through subunit- and sugar-dependent mechanisms , by which Nav activity is modulated