Regulation of voltage-dependent sodium channel expression in adrenal chromaffin cells - Involvement of multiple calcium signaling pathways

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 Ca2+ signaling pathways in cultured bovine adrenal chromaffin cells. Sustained, but not transient, elevation of intracellular Ca2+ concentration reduced the number of cell surface Na+ channels. The reduction of Na+ channels was suppressed by an inhibitor of calpain, a Ca2+-dependent protease, and by an inhibitor of protein kinase C (PKC). The activation of conventional PKC-alpha and novel PKC-epsilon reduced cell surface Na+ channels by the acceleration of internalization of the channels and by the increased degradation of Na+ channel alpha-subunit mRNA, respectively. On the contrary, the activation of PKC-epsilon increased Na+ channel beta(1)-subunit mRNA level. The inhibition of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase 2B, by immunosuppress ants upregulated cell surface Na+ channels by both stimulating externalization and inhibiting internalization of the channels without changing Na+ channel alpha- and beta(1)-subunit mRNA levels. Thus, the signal transduction pathways mediated by intracellular Ca2+ modulate cell surface Na+ channel expression via multiple Ca2+-dependent events, and the changes in the intracellular vesicular trafficking are the important mechanisms in the regulation of Na+ channel expression.