Investigations of the role of protein kinase C in the acute sedative effects of ethanol.
Investigations of the role of protein kinase C in the acute sedative effects of ethanol.
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研究蛋白激酶 C 在乙醇急性镇静作用中的作用。
DOI：
10.1111/j.1530-0277.1989.tb00413.x
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Baker,RC
中科院分区：
文献类型：
--
作者：
Deitrich,RA;Bludeau,PA;Baker,RC
研究了选择性饲养的抗（短睡眠）或敏感（长睡眠）小鼠对乙醇急性共济失调作用的全脑和脑区蛋白激酶C （PKC）活性。LS小鼠全脑PKC活性的胞浆和膜组分明显低于SS小鼠。脑区PKC活动在SS系和LS系之间存在显著差异。共济失调剂量的乙醇导致全脑细胞质部分和某些脑区PKC活性的显著增加，但在SS和LS小鼠中相同。体外添加乙醇使SS脑膜酶活性略有降低，提示体内给药后PKC活性增加的机制是间接的。这些结果表明PKC不参与LS和SS小鼠酒精敏感性差异的机制。直接在脑室内注射PKC激活剂肉豆蔻酸酯佛波酯（PMA）可增加SS和LS小鼠的睡眠时间。ICV注射PMA引起的LS小鼠体温下降也比SS小鼠明显。PMA在脑中的半衰期为9.6小时，未检测到代谢物。在有限的钙浓度下，PMA在体外激活PKC的效果在两个品系中都是一样的。然而，体外测定，给予ICV的PMA并没有改变PKC的水平。给LS小鼠腹腔注射肉豆蔻酸酯佛波酯（i.p）增加了它们对乙醇的睡眠时间反应，并导致单独给药时温度下降时间延长。与LS小鼠相比，对SS小鼠进行类似处理没有引起睡眠时间的改变或减少，体温下降也较小。腹腔注射PMA或PMA加乙醇对全脑细胞质或膜部分PKC活性没有影响，除了单独给予PMA的SS小鼠膜活性降低。研究发现，只有少量的PMA能到达大脑。佛波酯改变这些小鼠的睡眠时间似乎有不同的机制，一种是通过中枢效应，这与LS和SS小鼠的差异无关，另一种是通过外周效应，这可能与SS和LS的差异有关。
The activity of protein kinase C (PKC) in whole brain and brain areas of mice selectively bred for resistance (short sleep, SS) or sensitivity (long sleep, LS) to the acute ataxic effect of ethanol has been investigated. The cytosolic and membrane fractions of whole brain PKC activities are significantly less in LS mice than in SS mice. There are significant differences in PKC activity between brain areas in both the SS and LS lines. Ethanol given in ataxic doses results in significantly increased amounts in PKC activity in whole brain cytosolic fractions and in some brain areas but egually in both SS and LS mice. Ethanol added in vitro reduced enzyme activity slightly in SS brain membranes, suggesting that the mechanism of the increase in PKC activity seen after in vivo administration is indirect. These results indicate that PKC is not involved in the mechanism whereby LS and SS mice differ in alcohol sensitivity.Direct intracerebroventricular (ICV) injection of phorbol myristate acetate (PMA), an activator of PKC, resulted in increased sleep times in both SS and LS mice. ICV injection of PMA also caused a more marked decrease in body temperature in LS than in SS mice. The half‐life of PMA in brain was determined to be 9.6 hr and no metabolites could be detected.At limiting calcium concentrations, PMA added in vitro activated PKC equally well in both lines. However, PMA given ICV did not alter the level of PKC as determined in vitro.Administration of phorbol myristate‐acetate intraperitoneally (i.p.) to LS mice increased their sleep time response to ethanol and caused a prolonged depression of temperature when given alone. Similar treatment of SS mice caused no change or a decreased sleep time and a smaller temperature drop as compared to LS mice. There was no effect of i.p.‐administered PMA or PMA plus ethanol on PKC activity in whole brain cytosol or membrane fraction except for a decreased activity in membranes of SS mice given PMA alone. It was found that only small amounts of PMA given i.p. reached the brain. There appears to be different mechanisms by which phorbol esters alter sleep time in these mice, one via a central effect which is not related to why LS and SS mice differ and one via a peripherial effect that may be related to the SS and LS differences.