Protein Kinase C Participates in Up‐Regulation of Dihydropyridine‐Sensitive Calcium Channels by Ethanol

: Exposure to ethanol for several days increases the expression of dihydropyridine‐sensitive, voltage‐dependent Ca2+ channels in brain and in the neural cell line PC12. Since protein phosphorylation is a major mechanism by which ion channels are regulated, we used protein kinase inhibitors to investigate whether ethanol‐induced up‐regulation of Ca2+ channels involves activation of a protein kinase. Sphingosine and polymixin B, which inhibit protein kinase C and calmodulin‐dependent kinases, prevented the enhancement of 45Ca2+ uptake induced by exposure of PC12 cells to ethanol for 4 days. In addition, sphingosine blocked the ability of ethanol to increase the number of [3H]dihydropyridine binding sites in PC12 cell membranes. Sphingosine's effect was prevented by simultaneous exposure to phorbol 12,13‐dibutyrate, a potent activator of protein kinase C. Therefore, protein kinase C appears to be involved in the up‐regulation of dihydropyridine‐sensitive Ca2+ channels during prolonged exposure to ethanol.