Protein kinase Cdelta regulates ethanol intoxication and enhancement of GABA-stimulated tonic current.
Ethanol alters the distribution and abundance of PKCdelta in neural cell lines. Here we investigated whether PKCdelta also regulates behavioral responses to ethanol. PKCdelta(-/-) mice showed reduced intoxication when administered ethanol and reduced ataxia when administered the nonselective GABA(A) receptor agonists pentobarbital and pregnanolone. However, their response to flunitrazepam was not altered, suggesting that PKCdelta regulates benzodiazepine-insensitive GABA(A) receptors, most of which contain delta subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKCdelta overlapped with GABA(A) delta subunits in thalamus and hippocampus, and ethanol failed to enhance tonic GABA currents in PKCdelta(-/-) thalamic and hippocampal neurons. Moreover, using an ATP analog-sensitive PKCdelta mutant in mouse L(tk(-)) fibroblasts that express alpha4beta3delta GABA(A) receptors, we found that ethanol enhancement of GABA currents was PKCdelta-dependent. Thus, PKCdelta enhances ethanol intoxication partly through regulation of GABA(A) receptors that contain delta subunits and mediate tonic inhibitory currents. These findings indicate that PKCdelta contributes to a high level of behavioral response to ethanol, which is negatively associated with risk of developing an alcohol use disorder in humans.
Choi
Doo-Sup
DS
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, USA.
Wei
Weizheng
W
Deitchman
J Kevin
JK
Kharazia
Viktor N
VN
Lesscher
Heidi M B
HM
McMahon
Thomas
T
Wang
Dan
D
Qi
Zhan-Heng
ZH
Sieghart
Werner
W
Zhang
Chao
C
Shokat
Kevan M
KM
Mody
Istvan
I
Messing
Robert O
RO
D020268:Alcohol-Induced Disorders, Nervous System / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D051745:Protein Kinase C-delta / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D013788:Thalamus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
D002492:Central Nervous System Depressants; D018755:GABA Agonists; D021122:Protein Subunits; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D051745:Protein Kinase C-delta