ETHANOLS ACTIONS IN GAMMA PKC NULL MUTANTS

蛋白质磷酸化是细胞过程的基本调节因子。一 基因家族，钙/脂激活蛋白激酶C(PKC)编码 至少11个同工型。在这些同工型中，y-pkc同工型是唯一的 PKC仅在大脑和脊髓的神经元中表达。直到 产生携带被破坏的y-PKC的零突变小鼠(“敲除”) 基因，一直很难分析特定的同工型在 行为、生化和生理过程。 我们之前已经证明了y-PKC零突变体较少 对低温诱导和镇静催眠作用敏感 酒精与它们的野生窝产仔相比。我们在这里提供数据 表明y-PKC突变体不会对某些酒精产生耐受性 效果。因此，pkc的y-异型可能起到一定的作用。 在乙醇行动的调解中。 这项提议的目的是研究y-PKC在 测定急性和慢性乙醇治疗的行为反应。 在特定的目标#1中，y-PKC缺失突变体将与 是野生型或杂合型突变，使用几个 测量初始敏感度和容忍度。在具体目标2中， 将建立过表达y-PKC的转基因小鼠系并 以对乙醇的初始敏感性和耐受性为特点。一个 Y-PKC缺失突变体的遗传挽救也将由一个 转基因和零突变之间的遗传杂交。 这些研究的结果将确定y-PKC是否发挥作用 在乙醇的药理作用中，乙醇是 酒精敏感性和耐受性的测定。

Protein phosphorylation is a basic regulator of cellular processes. One gene family, the calcium/lipid activated protein kinase C (PKC) encodes at least 11 isotypes. Among these isotypes the y-PKC isotype is the only PKC solely expressed in neurons of the brain and spinal cord. Until the creation of null mutant mice ("knock-outs") that carry a disrupted y-PKC gene, it has been difficult to analyze the role of specific isotypes in behavioral, biochemical, and physiological processes. We have previously demonstrated that y-PKC null mutants are less sensitive to the hypothermia-inducing and sedative-hypnotic effects of alcohol compared to their wild-type littermates. We provide data here showing that y-PKC mutants do not develop tolerance to some of alcohol's effects. Therefore, it appears that the y-isotype of PKC may play a role in the mediation of ethanol's action. The goal of this proposal is to investigate the role of y-PKC in determining behavioral responses to acute and chronic ethanol treatment. In specific aim #1, the y-PKC null mutants will be compared to mice that are either wild-type or heterozygous for the mutations using several measures of initial sensitivity and tolerance. In specific aim #2, transgenic mouse lines over-expressing y-PKC will be created and characterized for initial sensitivity and tolerance to ethanol. A genetic rescue of the y-PKC null mutants will also be performed by a genetic cross between transgenics and null mutants. The results of these studies will establish whether y-PKC plays a role in the pharmacological actions of ethanol that underlie the determination of ethanol sensitivity and tolerance.