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
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
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DOI：
10.1073/pnas.92.9.3658
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发表时间：
1995-04-25
影响因子：
11.1
通讯作者：
WEHNER, JM
中科院分区：
文献类型：
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作者：
HARRIS, RA;MCQUILKIN, SJ;WEHNER, JM
钙/磷脂依赖性蛋白激酶（蛋白激酶 C、PKC）被认为在 A 型 γ-氨基丁酸 (GABA(A)) 受体对乙醇的敏感性中发挥作用。我们测试了一系列缺乏 PKC γ 同工型 (PKC gamma) 的无效突变小鼠，以确定这种大脑特异性同工酶在乙醇敏感性中的作用。我们发现，该突变将小脑中 PKC γ 免疫反应性降低至不可检测的水平，但未改变 PKC α、β(I) 或 β(II) 亚型的水平。突变小鼠对乙醇对翻正反射丧失和体温过低的影响的敏感性降低，但对氟硝西泮或戊巴比妥的反应正常。同样，分离脑膜的 GABA(A) 受体功能表明，该突变消除了乙醇的作用，但没有改变氟硝西泮或戊巴比妥的作用。这些研究显示了乙醇与 GABA(A) 受体的独特相互作用，并表明蛋白激酶同工酶可能是乙醇反应遗传差异的决定因素。
Calcium/phospholipid-dependent protein kinase (protein kinase C, PKC) has been suggested to play a role in the sensitivity of gamma-aminobutyrate type A (GABA(A)) 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, GABA(A) 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 GABA(A) receptors and suggest protein kinase isoenzymes as possible determinants of genetic differences in response to ethanol.