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J Biol Chem, Vol. 273, Issue 26, 16409-16414, June 26, 1998

Protein Kinase C Mediates Ethanol-induced Up-regulation of L-type Calcium Channels

Edward H. Gerstin Jr., Thomas McMahon, Jahan Dadgar, and Robert O. Messing^¶

From the  Department of Neurology, Ernest Gallo Clinic and Research Center and the ^¶ Graduate Programs in Neuroscience and Biomedical Sciences, University of California, San Francisco, California 94110

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 expression of a PKC fragment that inhibits phorbol ester-induced PKC translocation largely prevented ethanol-induced increases in dihydropyridine binding and K⁺-stimulated ⁴⁵Ca²⁺ 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 ⁴⁵Ca²⁺ 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.

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