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PMID: 7731960 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Mutant mice lacking the gamma isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of gamma-aminobutyrate type A receptors.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 92 ·No. 9 ·1995-04-25 ·Pages 3658-62

Harris RA, McQuilkin SJ, Paylor R, Abeliovich A, Tonegawa S, Wehner JM

Abstract

Calcium/phospholipid-dependent protein kinase (protein kinase C, PKC) has been suggested to play a role in the sensitivity of gamma-aminobutyrate type A (GABAA) receptors to ethanol. We tested a line of null mutant mice that lacks the gamma isoform of PKC (PKC gamma) to determine the role of this brain-specific isoenzyme in ethanol sensitivity. We found that the mutation reduced the amount of PKC gamma immunoreactivity in cerebellum to undetectable levels without altering the levels of the alpha, beta I, or beta II isoforms of PKC. The mutant mice display reduced sensitivity to the effects of ethanol on loss of righting reflex and hypothermia but show normal responses to flunitrazepam or pentobarbital. Likewise, GABAA receptor function of isolated brain membranes showed that the mutation abolished the action of ethanol but did not alter actions of flunitrazepam or pentobarbital. These studies show the unique interactions of ethanol with GABAA receptors and suggest protein kinase isoenzymes as possible determinants of genetic differences in response to ethanol.

MeSH Terms
Animals Base Sequence Body Temperature/drug effects Cerebellum/drug effects,metabolism Cerebral Cortex/drug effects,metabolism Chlorides/metabolism DNA Primers Ethanol/blood,pharmacology Female Flunitrazepam/pharmacology Isoenzymes/deficiency,genetics,metabolism Male Mice Mice, Mutant Strains Molecular Sequence Data Pentobarbital/pharmacology Polymerase Chain Reaction Posture Protein Kinase C/deficiency,genetics,metabolism Receptors, GABA-A/drug effects,physiology Reflex/drug effects
Chemicals
Chlorides DNA Primers Isoenzymes Receptors, GABA-A Ethanol Flunitrazepam Protein Kinase C Pentobarbital
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Harris R A
Denver Veterans Affairs Medical Center, CO, USA.
McQuilkin S J
Paylor R
Abeliovich A
Tonegawa S
Wehner J M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.92.9.3658
Published
1995-04-25
Pages
3658-62
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC42020
Subset
IM
Grants
NIAAA NIH HHS · AA00141 · United States
NIAAA NIH HHS · AA03527 · United States
NIAAA NIH HHS · AA06399 · United States
Corrections
CommentIn
PMID: 7731956
External Links
PubMed source DOI: 10.1073/pnas.92.9.3658 PMC Full Text View journal details
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