Mutations in ion channels and their auxiliary subunits can lead to neurological or cardiovascular diseases called "channelopathies". In recent years it has become apparent that ion channels are part of large, multi-protein complexes, comprising not only the channel pore and its auxiliary subunits, but also components of the cytoskeleton, regulatory kinases and phosphatases, trafficking proteins, extracellular matrix proteins, and possibly even other ion channels. Sodium channel beta subunits do not form the ion-conducting pore, but are multifunctional proteins that play critical roles in modulation of channel function, regulation of channel expression levels at the plasma membrane, cell adhesion, neurite outgrowth, and transcription, Beta subunits signal through multiple pathways on multiple time scales in a tissue-specific, and possibly even subcellular domain-specific, manner. This feature makes sodium channels unique among the superfamily of voltage- and ligand-gated ion channels. In vitro evidence suggests that sodium channel beta subunits serve as critical communication links between adjacent cells, the extracellular environment, and intracellular signaling mechanisms, possibly including other ion channels. We propose that disruption of any member of a sodium channel signaling complex in vivo has the potential to disrupt channel function, resulting in paroxysmal disease, such as epilepsy or cardiac arrhythmia. In addition, because beta subunits can function as cell adhesion molecules in the absence of the ion conducting pore, mutations in beta subunit genes may result in defects in axon guidance or cell-cell communication. Consistent with this, Scn1b null mice have a hyperexcitable phenotype that includes epilepsy, ataxia, abnormal neuronal pathfinding, a prolonged QT interval, and early death. We have recently reported the first SCN1B human mutation linked to Dravet Syndrome, a severe and sometimes fatal childhood epileptic encephalopathy that also leads to mental retardation. In contrast to Scn1b null mice, Scn2b null mice have no spontaneous behavioral phenotype but are neuroprotective in a model of demyelinating disease and have a reduced response to neuropathic and inflammatory pain. We are now collaborating with Dr. Jack Parent and Dr. Miriam Meisler to study induced pluripotent stem cell neurons generated from patient skin cells to understand the mechanism of inherited epilepsy mutations in sodium channel genes. Understanding the molecular composition of individual sodium channel signaling complexes in excitable cells, as well as the conducting and non-conducting functions of the beta subunits may yield important insights into the molecular basis of inherited disease.
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