ETHANOL DISRUPTION OF CENTRAL MUSCARINIC TRANSMISSION

乙醇干扰中枢毒蕈碱传输

• 批准号: 3111525
• 负责人: Robert S. Aronstam
• 金额: $ 12.93万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3111525
• 关键词: G protein; adenylate cyclase; alcoholic beverage consumption; autoradiography; binding proteins; brain; butanols; centrifugation; chemical binding; cyclic AMP; enzyme mechanism; ethanol; gel filtration chromatography; guanine nucleotides; laboratory rat; membrane proteins; muscarinic receptor; neural transmission; phosphatidylinositols; phospholipids; physical chemical interaction; propanols; protein metabolism; proteolysis; receptor sensitivity; scintillation spectrometry; synapses; thin layer chromatography

The aim of the proposed research is to understand how ethanol affects the function of muscarinic acetylcholine receptor complexes in the brain. We have demonstrated that ethanol 1) alters ligand binding to the receptor and 2) disrupts receptor coupling to guanine nucleotide-dependent transducer proteins (G proteins). The latter effect represents a novel mechanism for disruption of synaptic transmission. The hypotheses to be tested are that ethanol interacts with muscarinic-G protein complexes in the brain, thereby affecting 1) ligand binding to the receptor, 2) gaunine nucleotide regulation of receptor binding, 3) receptor regulation of postsynaptic biochemical events, 4) guanine nucleotide binding to receptor-associated G proteins, and/or 5) the GTPase activity of G proteins. Accordingly, the Specific Aims of the proposed research are to determine the effects of ethanol and other short cahin alcohols on muscarinic (and other) receptors and their associated G proteins in rat brain. Receptor processes to be studied are 1) ligand binding, including antagonist binding site density, affinity, kinetics and thermodynamics, and agonist binding propetties (subpopulation distribution and affinities), 2) receptor-G protein coupling, as revealed by guanine nucleotide regulation of agonist binding, 3) muscarinic receptor-mediated inhibition of adenylate cyclase activity and stimulation of phosphatidylinositol breakdown in brain membranes, as an indication functional muscarinic transmission, and 4) the GTPase and (345)GTP binding activities of G protein species isolated from rat brain, to evaluate the possibility of direct alcohol-G protein interactions. This research will increase our understanding of muscarinic receptor organization and function in the brain and provide insight into the molecular bases for ethanol disruption of synaptic transmission.

拟议研究的目的是了解乙醇 影响毒蕈碱乙酰胆碱受体的功能 大脑中的复合物。 我们已经证明了乙醇1） 改变配体与受体结合，2）破坏受体 与鸟嘌呤核苷酸依赖性换能蛋白的偶联（G 蛋白质）。 后一种效果代表了一种新型机制 突触传播的破坏。 要测试的假设 乙醇与毒蕈碱-G蛋白复合物相互作用 大脑，因此影响1）配体与受体结合，2） Gaunine核苷酸的受体结合调节，3）受体 调节突触后生化事件，4）鸟嘌呤 核苷酸与受体相关的G蛋白结合，/或5） G蛋白的GTPase活性。 因此，拟议研究的具体目的是 确定乙醇和其他短葡萄酒对乙醇的影响 毒蕈碱（和其他）受体及其相关的G蛋白 在大鼠大脑中。 要研究的受体过程是1）配体 结合，包括拮抗剂结合位点密度，亲和力， 动力学和热力学，以及激动剂结合预言 （亚群分布和亲和力），2）受体-G蛋白 偶联，如鸟嘌呤核苷酸调节激动剂的调节 结合，3）毒蕈碱受体介导的腺苷抑制 磷脂酰肌醇分解的循环酶活性和刺激 在脑膜中，作为一种功能性毒蕈碱的指示 传输和4）GTPase和（345）GTP结合活动 从大鼠大脑分离的G蛋白质物种，以评估 直接酒精-G蛋白相互作用的可能性。 这项研究将增加我们对毒蕈碱的理解 受体组织和大脑的功能并提供洞察力 进入分子碱基，以破坏突触的乙醇 传播。

项目成果

Colchicine inhibits acetylcholine receptor stimulation of G protein GTPase activity in rat striatum.

秋水仙碱抑制大鼠纹状体中 G 蛋白 GTP 酶活性的乙酰胆碱受体刺激。

• DOI: 10.1111/bcpt.1991.69.4.259
• 发表时间: 1991
• 期刊: Pharmacology & toxicology
• 作者: Ravindra,R;Aronstam,RS
• 通讯作者: Aronstam,RS

Volatile anesthetics and NMDA receptors. Enflurane inhibition of glutamate-stimulated [3H]MK-801 binding and reversal by glycine.

挥发性麻醉剂和 NMDA 受体。

• DOI: 10.1016/0304-3940(91)90436-w
• 发表时间: 1991
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Martin,DC;Abraham,JE;Plagenhoef,M;Aronstam,RS
• 通讯作者: Aronstam,RS

Halothane disruption of alpha 2-adrenergic receptor-mediated inhibition of adenylate cyclase and receptor G-protein coupling in rat brain.

氟烷破坏大鼠脑中 α2-肾上腺素能受体介导的腺苷酸环化酶和受体 G 蛋白偶联的抑制作用。

• DOI: 10.1016/0006-2952(90)90672-8
• 发表时间: 1990
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Baumgartner,MK;Dennison,RL;Narayanan,TK;Aronstam,RS
• 通讯作者: Aronstam,RS

Influence of volatile anesthetics on muscarinic regulation of adenylate cyclase activity.

挥发性麻醉剂对腺苷酸环化酶活性的毒蕈碱调节的影响。

• DOI: 10.1016/0006-2952(90)90702-m
• 发表时间: 1990
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Anthony,BL;Dennison,RL;Aronstam,RS
• 通讯作者: Aronstam,RS

Stimulation of the release of [32P]guanosine 5'-diphosphate from G proteins in the rat anterior pituitary lobe by gonadotrophin-releasing and thyrotrophin-releasing hormones.

促性腺激素释放激素和促甲状腺激素释放激素刺激大鼠垂体前叶 G 蛋白释放 [32P]鸟苷 5-二磷酸。

• DOI: 10.1530/jrf.0.0950669
• 发表时间: 1992
• 期刊: Journal of reproduction and fertility
• 作者: Ravindra,R;Aronstam,RS
• 通讯作者: Aronstam,RS