MOLECULAR AND CELLULAR NEUROPHYSIOLOGY OF BUTYROLACTONES & RELATED COMPOUNDS

丁内酯的分子和细胞神经生理学

• 批准号: 6204992
• 负责人: STEVEN ROTHMAN
• 金额: $ 10.35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6204992
• 关键词: Drosophilidae; GABA receptor; anticonvulsants; brain electrical activity; butyrolactone; drug receptors; electrophysiology; evoked potentials; gamma aminobutyrate; hippocampus; laboratory rat; membrane channels; mycotoxins; neurons; neuropharmacology; newborn animals; picrotoxin; protein structure function; receptor binding; tissue /cell culture; transfection; voltage /patch clamp

The GABA-A receptor/ionophore complex is responsible for most fast inhibition in the mammalian brain. Activation of this receptor increases the flux of chloride across the neuronal plasma membrane, which typically hyperpolarizes the neuron and diminishes the probability of firing action potentials. Several modulatory sites that modify the effect of GABA on this receptor/ionophore complex have been identified over the last decade. Drugs that act at these sites and diminish GABA-induced currents are usually convulsants; conversely, drugs that potentiate GABA currents are often anticonvulsants. We are particularly interested in a picrotoxin site(s) and its modulation by a series of gamma-butyrolactones that have been synthesized in our laboratories. We have previously shown that different substitute butyrolactones can either enhance ("GABA+") or block ("GABA-") GABA-induced chloride currents. In the electrophysiology core of this program project application, we plan to: 1. Characterize new gamma-butyrolactones that appear to have promise as clinical anticonvulsants. We are particularly interested in studying derivatives of the compound aflatrem, which is almost 1000 times more potent than other gamma-butyrolactones in augmenting GABA-induced currents. We shall also investigate lactone optical isomers, which may be more potent and selective for this site. 2. Define the detailed mechanism(s) of action of these compounds. We believe these compounds act at two distinct sites that are within the M2 transmembrane segment of the GABA-A subunits. We shall use a variety of GABA-A receptor subunit mutants to attempt to confirm this. We shall also investigate the hypothesis that arachidonic acid may be a natural ligand for this site. 3. Evaluate the modulation of other ion channels by this class of compounds. We already know that certain lactones potentiate nicotinic cholinergic currents in hippocampal neurons. Based on sequence homology with the GABA-A receptor subunits, we expect that glycine, serotonin, and homomeric receptors composed of pi1 GABA subunits should also respond to gamma-butyrolactones. The planned experiments will use standard electrophysiological techniques to characterize GABA-A receptors and inhibitory currents in rat neurons and also receptor subunits transfected into a kidney cell line. We expect this work to have therapeutic implications for a number of medical, neurological, and psychiatric diseases, especially epilepsy.

GABA-A受体/离子载体复合物负责大多数快速 哺乳动物大脑中的抑制作用。这种受体的激活增加 氯离子穿过神经元质膜的通量， 使神经元超极化，并减少放电动作的可能性 潜力几个调节GABA作用的调节位点 这种受体/离子载体复合物在过去十年中已经被鉴定。 作用于这些部位并减少GABA诱导电流的药物是 通常是惊厥药;相反，增强GABA电流的药物是 通常是抗惊厥药我们对印防己毒素特别感兴趣 位点及其通过一系列γ-丁内酯的调节， 是在我们的实验室里合成的。我们之前已经证明， 不同取代的丁内酯可以增强（“GABA+”）或阻断（“GABA+”） （“GABA-”）GABA诱导的氯电流。 在电生理学的核心这个程序项目的应用，我们计划 收件人： 1.描述新的γ-丁内酯，这些内酯似乎有希望作为 临床抗惊厥药。我们特别感兴趣的是 化合物的衍生物，这是几乎1000倍以上 比其他γ-丁内酯在增强GABA诱导的 水流我们还将研究内酯光学异构体，这可能是 对这个网站更有效更有选择性 2.定义这些化合物的详细作用机制。我们 我相信这些化合物作用于M2中的两个不同部位 GABA-A亚基的跨膜片段。我们将使用各种 GABA-A受体亚单位突变体试图证实这一点。我们亦会 研究花生四烯酸可能是一种天然配体的假设 此网站的。 3.评价这类化合物对其他离子通道的调节作用。 化合物.我们已经知道，某些内酯增强烟碱 海马神经元的胆碱能电流。基于序列同源性 与GABA-A受体亚单位，我们预计，甘氨酸，血清素， 由pi 1 GABA亚单位组成的同源受体也应该响应于 γ-丁内酯 计划中的实验将使用标准的电生理技术 表征大鼠神经元中的GABA-A受体和抑制电流 以及转染到肾细胞系中的受体亚单位。我们预计 这项工作对许多医学， 神经和精神疾病，特别是癫痫。