Regulation of Voltage‐Dependent Sodium Channel Expression in Adrenal Chromaffin Cells

A bstract : The density and electrical activity of cell surface voltage‐dependent Na + channels are key determinants regulating the neuronal plasticity including development, differentiation, and regeneration. Abnormalities of Na + channels are associated with various neurological diseases. In this paper, we review the regulatory mechanisms of cell surface Na + channel expression mediated by Ca 2+ signaling pathways in cultured bovine adrenal chromaffin cells. Sustained, but not transient, elevation of intracellular Ca 2+ concentration reduced the number of cell surface Na + channels. The reduction of Na + channels was suppressed by an inhibitor of calpain, a Ca 2+ ‐dependent protease, and by an inhibitor of protein kinase C (PKC). The activation of conventional PKC‐α and novel PKC‐ε reduced cell surface Na + channels by the acceleration of internalization of the channels and by the increased degradation of Na + channel α‐subunit mRNA, respectively. On the contrary, the activation of PKC‐ε increased Na + channel β 1 ‐subunit mRNA level. The inhibition of calcineurin, a Ca 2+ /calmodulin‐dependent protein phosphatase 2B, by immunosuppressants upregulated cell surface Na + channels by both stimulating externalization and inhibiting internalization of the channels without changing Na + channel α‐ and β 1 ‐subunit mRNA levels. Thus, the signal transduction pathways mediated by intracellular Ca 2+ modulate cell surface Na + channel expression via multiple Ca 2+ ‐dependent events, and the changes in the intracellular vesicular trafficking are the important mechanisms in the regulation of Na + channel expression.