Brief ethanol exposure inhibits L-type, voltage-gated calcium channels in neural cells, whereas chronic exposure increases the number of functional channels. In PC12 cells, this adaptive response is mediated by protein kinase C (PKC), but the PKC isozyme responsible is unknown. Since chronic ethanol exposure increases expression of PKC␦ and PKC⑀, we investigated the role these isozymes play in up-regulation of L-type channels by ethanol. Incubation with the PKC inhibitor GF 109203X or

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... of a PKC␦ fragment that inhibits phorbol ester-induced PKC␦ translocation largely prevented ethanol-induced increases in dihydropyridine binding and K ؉ -stimulated 45 Ca 2؉ uptake. A corresponding PKC⑀ fragment had no effect on this response. These findings indicate that PKC␦ mediates up-regulation of L-type channels by ethanol. Remaining responses to ethanol in cells expressing the PKC␦ fragment were not inhibited by GF 109203X, indicating that PKC␦-independent mechanisms also contribute. PKC␦ overexpression increased binding sites for dihydropyridine and L-channel antagonists, but did not increase K ؉ -stimulated 45 Ca 2؉ uptake, possibly because of homeostatic responses that maintain base-line levels of channel function. Since L-type channels modulate drinking behavior and contribute to neuronal hyperexcitability during alcohol withdrawal, these findings suggest an important role for PKC␦ in alcohol consumption and dependence.