Physiological function of voltage-dependent Na^+ channel β-subunit as an adhesion molecule

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Voltage-dependent Na^+ channel β-subunits contain a single extracellular Ig-like domain with structural similarity to the cell adhesion molecules. In this project, we have studied the regulatory mechanisms of expression and intracellular trafficking of the β-subunits as well as their role in cell differentiation.In cultured bovine adrenal chromaffin cells, insulin and IGF-1 increased cell surface expression of Na^+ channels. Insulin and IGF-1 increased Na^+ channel α-subunit mRNA level but not (β-subunit mRNA level. In rat pheochromocytoma PC 12 cells, neuronal differentiation by nerve growth factor increased β_1-subunit mRNA level but not β_3-subunit mRNA level, indicating that the mechanisms regulating the expression of a-subunit and β-subunits are different.When HEK293 cells were transfected with GFP tagged β-subunit constructs, β_1-Subunit-GFP was expressed strongly at the cell surface and weakly in endoplasmic reticulum. β_2-Subunit-GFP was expressed predominantly at cell surface, and these cells extended many microvilli. β_3-Subunit-GFP was expressed strongly at cell membrane and at intracellular spherical membrane structure, and these cells also extended microvilli, indicating that the intracellular trafficking and the physiological function of the β-subunits are different. In addition, PC12 cells expressing each subunit tagged with GFP extended neuritis even in the absence of nerve growth factor, and the effects of β_2-GFP or β_3-GFP were stronger than that of β_1-GFP. The neurite extending effects of nerve growth factor were more pronounced in each β-subunit-GFP expressing cells than in the control cells.These results indicate that β-subunits play a role in the regulation of cell differentiation, and that the intracellular trafficking mechanisms of the β-subunits and their regulatory mechanisms of expression are different.