ANTICONVULSANT REGULATION OF GABA CHLORIDE CHANNELS

GABA 氯化物通道的抗惊厥调节

• 批准号: 3084128
• 负责人: ROY E TWYMAN
• 金额: $ 6.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3084128
• 关键词: anticonvulsants; barbiturates; benzodiazepines; chloride channels; chlorine; evoked potentials; gamma aminobutyrate; laboratory mouse; membrane channels; membrane potentials; neurons; neuropharmacologic agent; neurotransmitter receptor; tissue /cell culture; voltage /patch clamp

In an effort to understand the physical and pharmacologic properties of benzodiazepine and barbiturate anticonvulsants, we will investigate GABA/benzodiazepine/-barbiturate ligand and receptor interactions. We will characterize GABA evoked single channel chloride currents and the regulation of these currents by benzodiazepine and barbiturate receptor agonists and inverse agonists. The anticonvulsant activity of benzodiazepines and barbiturates may in part be mediated by potentiating GABA inhibition of neuronal excitability. Intracellular recordings have shown the potentiation to be produced by increasing and/or prolonging GABA-evoked whole cell chloride currents but the mechanisms appear to be different and are poorly understood. The whole cell chloride currents are composed of many smaller ionic currents conducted through channels in the membrane and the channels open and close briefly when activated. A key to understanding how the anticonvulsants effect their differential response is to investigate the coupling between ligand binding and the gating properties or kinetic behavior of opening and closing of the chloride channel. Ligands may alter the frequency of channel opening and closing through modification of receptor binding and/or alter the physical properties of channel gating. Intracellular recording techniques and noise frequency analysis cannot resolve the complex behavior and mechanisms of channel gating. Newly developed patch clamp techniques, which enable direct recording of single ion channel currents, will be used in performing studies on mouse spinal cord and cortical neurons in primary dissociated cell culture. Emphasis will be placed upon identification and characterization of the conductances involved and the mechanisms of action between ligand binding and the regulation of opening and closing of the GABA/benzodiazepine/barbiturate chloride channel complex. The goal is to establish how benzodiazepine and barbiturate anticonvulsants potentiate GABA inhibition by investigation of their actions ar the single ion channel/ receptor level.

为了理解物理和药理学 苯二氮卓类和巴比妥类抗惊厥药的性质，我们 将研究GABA/苯二氮卓类/-巴比妥酸盐配体， 受体相互作用 我们将描述GABA诱发的单个 通道氯电流和这些电流的调节， 苯并二氮杂卓和巴比妥酸盐受体激动剂和反 激动剂 苯二氮卓类和巴比妥类药物的抗惊厥活性可能 部分地通过增强GABA对神经元抑制来介导 兴奋性 细胞内记录显示 通过增加和/或延长GABA诱发的整体 细胞氯电流，但机制似乎不同 而且人们对它知之甚少。 全细胞氯电流为 由许多较小的离子电流通过通道传导组成 在细胞膜上，当细胞膜破裂时， 激活 了解抗惊厥药物如何发挥作用的关键 他们的不同反应是研究 配体结合和门控性质或动力学行为 氯离子通道的打开和关闭。 配体可以改变 通过修改通道打开和关闭频率 受体结合和/或改变通道的物理性质 门控 细胞内记录技术和噪声频率 分析不能解决复杂的行为和机制， 通道选通 新开发的膜片钳技术， 使单离子通道电流的直接记录，将是 用于对小鼠脊髓和皮质进行研究 原代分离细胞培养中的神经元。 重点将 放置在电导的识别和表征上 参与和配体结合之间的作用机制， 开放和关闭的规则 GABA/苯二氮卓类/巴比妥类氯化物通道复合物。 我们的目标是确定苯二氮卓类药物和巴比妥类药物 通过研究抗惊厥药增强GABA抑制作用， 它们的作用是单离子通道/受体水平。