Voltage-gated Na+ Channels: Not Just for Conduction.

[摘要] Voltage-gated sodium channels (VGSCs), composed of a pore-forming alpha subunit and up to two associated Beta subunits, are critical for the initiation of the action potential in excitable tissues. VGSC Beta subunits, first cloned in 1992, modulate sodium current but also play non-conducting roles as cell adhesion molecules that allow them to function in the processes of neuronal migration, neurite outgrowth, pathfinding, and axonal fasciculation. Mutations in VGSC alpha and Beta genes are associated with diseases caused by dysfunction of excitable tissues such as epilepsy. SCN1B-C121W, the first epilepsy-associated sodium channel mutation identified, results in Genetic Epilepsy with Febrile Seizures plus (GEFS+). This mutation in SCN1B, which encodes the VGSC Beta1/ Beta1B subunits, disrupts sodium current modulation and cell adhesive functions of Beta1 in vitro. The goal of my thesis research was to compare mice heterozygous for Scn1b-C121W (Scn1b+/W) with mice heterozygous for the Scn1b null allele (Scn1b+/-) to ask whether the C121W mutation results in loss-of-function in vivo. I found that Scn1b+/W mice were more susceptible than Scn1b+/- and Scn1b+/+ mice to hyperthermia-induced seizures, a model for pediatric febrile seizures. Importantly, Beta1-C121W subunits are expressed at the neuronal cell surface in vivo. However, Beta1-C121W polypeptides are incompletely glycosylated and do not associate biochemically with VGSC alpha subunits. Beta1-C121W localization is restricted to the neuronal cell body in Scn1bW/W mice and is not detected at optic nerve nodes of Ranvier or axon initial segments in the cortex or cerebellum. These data, taken together with our previous results showing that Beta1-C121W cannot participate in trans homophilic cell adhesion, lead to the hypothesis that SCN1B-C121W confers a deleterious gain-of-function. Beta1-C121W expression in brain may dilute the density of Beta1-WT subunits at the plasma membrane and thus effectively reduce the level of Beta1 functionality in neurons. In addition, Beta1-mediated trans homophilic cell-cell adhesion may be particularly disrupted in this mechanism, since WT-mutant or mutant-mutant Beta1 subunit pairs may be aligned, but not associated, in trans on adjacent axons, resulting in areas of aberrant adhesion and fasciculation.

[发布机构] University of Michigan

[效力级别] pediatric epilepsy mouse model

[关键词] Voltage-gated sodium channel beta1 subunit;pediatric epilepsy mouse model;SCN1B;GEFS+;Molecular;Cellular and Developmental Biology;Neurosciences;Pharmacy and Pharmacology;Physiology;Health Sciences;Science;Pharmacology