ETHANOLS ACTIONS IN GAMMA PKC NULL MUTANTS

乙醇在 GAMMA PKC 无效突变体中的作用

• 批准号: 2841998
• 负责人: JEANNE M WEHNER
• 金额: $ 25.56万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2841998
• 关键词: behavioral habituation /sensitization; body physical activity; body temperature regulation; drug tolerance; ethanol; genetically modified animals; isozymes; laboratory mouse; pharmacogenetics; pharmacokinetics; phosphorylation; protein kinase C

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.

蛋白质磷酸化是细胞过程的基本调节剂。一 钙/脂质激活蛋白激酶C（PKC）基因家族，其编码 至少有11种同种型。在这些同种型中，γ-PKC同种型是唯一的 PKC仅在脑和脊髓的神经元中表达。直到 产生携带破坏的γ-PKC的无效突变小鼠（“敲除”） 基因，很难分析特定同种型的作用， 行为、生物化学和生理过程。 我们以前已经证明，γ-PKC无效突变体， 对低血糖诱导和镇静催眠作用敏感 与野生型同窝仔相比，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， 方面的影响.因此，PKC的y-同种型可能发挥作用， 在乙醇的作用中起了中介作用。 本研究的目的是探讨γ-PKC在细胞凋亡中的作用。 确定对急性和慢性乙醇治疗的行为反应。 在具体目标#1中，将γ-PKC无效突变体与 是野生型或杂合的突变，使用几种 初始敏感性和耐受性的测量。在具体目标#2中， 将建立过表达γ-PKC的转基因小鼠系， 其特征在于对乙醇的初始敏感性和耐受性。一 y-PKC无效突变体的遗传拯救也将由 转基因和无效突变体之间的遗传杂交。 这些研究的结果将确定γ-PKC是否在 在乙醇的药理作用中， 乙醇敏感性和耐受性的测定。