Ethanol regulation of D(1) dopamine receptor signaling is mediated by protein kinase C in an isozyme-specific manner.
Ethanol consumption potentiates dopaminergic signaling that is partially mediated by the D(1) dopamine receptor; however, the mechanism(s) underlying ethanol-dependent modulation of D(1) signaling is unclear. We now show that ethanol treatment of D(1) receptor-expressing cells decreases D(1) receptor phosphorylation and concurrently potentiates dopamine-stimulated cAMP accumulation. Protein kinase C (PKC) inhibitors mimic the effects of ethanol on D(1) receptor phosphorylation and dopamine-stimulated cAMP levels in a manner that is non-additive with ethanol treatment. Ethanol was also found to modulate specific PKC activities as demonstrated using in vitro kinase assays where ethanol treatment attenuated the activities of lipid-stimulated PKCgamma and PKCdelta in membrane fractions, but did not affect the activities of PKCalpha, PKCbeta(1), or PKCvarepsilon. Importantly, ethanol treatment potentiated D(1) receptor-mediated DARPP-32 phosphorylation in rat striatal slices, supporting the notion that ethanol enhances D(1) receptor signaling in vivo. These findings suggest that ethanol inhibits the activities of specific PKC isozymes, resulting in decreased D(1) receptor phosphorylation and enhanced dopaminergic signaling.
Rex
Elizabeth B
EB
Molecular Neuropharmacology Section, National Institute on Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Rankin
Michele L
ML
Ariano
Marjorie A
MA
Sibley
David R
DR
D020268:Alcohol-Induced Disorders, Nervous System / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D002492:Central Nervous System Depressants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C497930:Ppp1r1b protein, rat; D017447:Receptors, Dopamine D1; D000431:Ethanol; D000242:Cyclic AMP; C087857:protein kinase C gamma; D011493:Protein Kinase C; D051745:Protein Kinase C-delta