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J Biol Chem. 1998 Jun 26;273(26):16409-14.

Protein kinase Cdelta mediates ethanol-induced up-regulation of L-type calcium channels.

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  • 1Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California 94110, USA.


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 PKCdelta and PKCepsilon, 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 PKCdelta fragment that inhibits phorbol ester-induced PKCdelta translocation largely prevented ethanol-induced increases in dihydropyridine binding and K+-stimulated 45Ca2+ uptake. A corresponding PKCepsilon fragment had no effect on this response. These findings indicate that PKCdelta mediates up-regulation of L-type channels by ethanol. Remaining responses to ethanol in cells expressing the PKCdelta fragment were not inhibited by GF 109203X, indicating that PKCdelta-independent mechanisms also contribute. PKCdelta 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 PKCdelta in alcohol consumption and dependence.

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