REGULATION OF THE GABA RECEPTOR-CHLORIDE ION CHANNEL

GABA 受体-氯离子通道的调节

• 批准号: 3476685
• 负责人: Rochelle D. Schwartz-Bloom
• 金额: $ 9.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 1992-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3476685
• 关键词: anticonvulsants; autoradiography; barbiturates; benzodiazepines; brain disorder chemotherapy; brain metabolism; chemical binding; dosage; drug metabolism; electrostimulus; epilepsy; gamma aminobutyrate; membrane lipids; membrane permeability; neuropharmacology; phospholipids; radiotracer; superoxides; tissue /cell culture

The overall objective is to determine the mechanisms of regulation of the GABA receptor/chloride (C1-) ion channel complex in rat brain. Since abnormal GABAergic neurotransmission appears to be a major factor in seizure disorders, regulation of the 'transducer' component (the GABA receptor/C1- ion channel) of GABA-ergic transmission may play an important role in the etiology and response to seizure activity. Two major biochemical tools will be used to achieve these objectives. One involves studies of the regulation of GABA receptor-gated C1- ion channel binding sites labeled with (35S)TBPS. The other involves studies of the regulation of GABA receptor-mediated 36C1- ion flux. An important feature of these techniques is that they can be used in the same tissue from the same animals under identical conditions, something that was not possible in the past. The research plan is divided into 3 parts. The first is to determine the cellular mechanisms of regulation in vitro. Alterations in GABA receptor/C1- ion channel activity will be measured subsequent to 1) desensitizing conditions 2) alterations in membrane phospholipids by phospholipases (i.e., release of free fatty acids and subsequent formation of oxygen radicals and lipid peroxides) and 3) exposure to phosphorylating conditions. The role of these cellular processes in regulating the GABA receptor complex in vivo will be determined in the second and third parts of the research plan. In the second part, alterations in the sensitivity of the GABA receptor/C1- ion channel will be studied following repeated exposure of rats to agonists off the GABA receptor complex which are known to down-regulate GABA recognition sites. These drugs which act at 3 distinct sites on the GABA receptor complex include GABA agonists, benzodiazepines and barbiturates. Each of these drugs has anticonvulsant activity. In the third part studies are designed to measure changes in GABA receptor/C1- ion channel activity following both chemically- and electrically-induced seizures. Convulsants which act at distinct sites on the GABA receptor complex (bicuculline and picrotoxin) and maximal electroshock will be administered repeatedly over a 10 day period. The studies will provide new insights into the mechanisms that regulate GABAergic neurotransmission on a cellular level. This research should reveal the importance of these mechanisms in the actions of convulsant and anticonvulsant drugs and in the physiology of seizure activity itself.

总的目标是要确定的监管机制， 大鼠脑内GABA受体/氯离子通道复合物。 以来 GABA能神经传递异常似乎是 癫痫发作障碍，调节'换能器'组件（GABA 受体/C1-离子通道）的GABA能传递可能发挥重要作用， 在病因学和对癫痫发作活动的反应中的作用。 两大 将使用生物化学工具来实现这些目标。 一个涉及 GABA受体门控C1-离子通道结合调节的研究 标记有（35 S）TBPS的位点。 另一个是关于监管的研究 GABA受体介导的36 C1离子流。 其中的一个重要特征是 技术的另一个优点是，它们可以用于来自相同组织的相同组织。 动物在相同的条件下，这是不可能的， 过去 研究计划分为三个部分。 一是 确定体外调节的细胞机制。 的改变 GABA受体/C1-离子通道活性将在1） 脱敏条件2）膜磷脂的改变， 磷脂酶（即，游离脂肪酸的释放和随后的形成 氧自由基和脂质过氧化物）和3）暴露于磷酸化 条件 这些细胞过程在调节GABA 第二部分和第三部分将测定体内受体复合物 的研究计划。 在第二部分中， GABA受体/C1-离子通道的研究将在重复 大鼠暴露于GABA受体复合物的激动剂， 下调GABA识别位点。 这些药物在3 GABA受体复合物上的不同位点包括GABA激动剂， 苯二氮卓类和巴比妥类药物。 每种药物都有抗惊厥作用 活动 在第三部分中，研究旨在测量 GABA受体/C1-离子通道活性， 电诱发癫痫 作用于不同部位的惊厥药 GABA受体复合物（荷包牡丹碱和印防己毒素）和最大 将在10天的时间内重复施用电击。 的 这些研究将为调节 细胞水平上的GABA能神经传递。 这项研究应该 揭示了这些机制在惊厥和 抗惊厥药物和癫痫发作活动本身的生理学。