CONSTITUTIVELY ACTIVE SEROTONIN RECEPTORS

组成型活性血清素受体

• 批准号: 6724895
• 负责人: Milton Teitler
• 金额: $ 31万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6724895
• 关键词: G protein; antiemetics; antipsychotic agents; chlorpromazine; clozapine; confocal scanning microscopy; cyclic AMP; green fluorescent proteins; haloperidol; intracellular transport; morpholine; mutant; neuropharmacology; pharmacokinetics; phenylamide; pimozide; prochlorperazine; protein structure function; receptor binding; risperidone; serotonin receptor; site directed mutagenesis; thioridazine; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): We have shown that clozapine and risperidone, atypical antipsychotic drugs, have potent inverse agonist properties at constitutively activated mutant (CAM) forms of the rat 5SHT2A and 5HT2C receptors. Inverse agonist activity may be a significant property of antipsychotic drugs, given the revised ternary complex model of G-protein coupled receptors (GPCR), which predicts a steady-state level of activation of receptors in the absence of ligand stimulation. Further studies of antipsychotic drug actions at CAM forms of clozapine-sensitive human SHT receptors are necessary to determine if inverse agonist activity is a key property of atypical antipsychotic drugs. In order to expand the studies to the human 5HT6 and 5HT7 receptors we have attempted to make CAM forms of these receptors by mutating two well-documented regions of GPCR constitutive activity. Initial experiments involving mutations in these areas have produced forms of the receptor either lacking robust constitutive activity or producing apparently null mutant forms of the receptor (5HT6). While these results have slowed progress on determining the inverse agonist activity of antipsychotic drugs on these receptors they open up interesting avenues of research on the variability in structure within the GPCR family and within 5HT receptors in particular. Therefore we propose to pursue three specific aims: 1) we will continue to test typical and atypical antipsychotic drugs at human CAM forms of the 5HT2A and 5HT2C receptors; 2) we will continue to mutate the human 5HT6 and 5HT7 receptors to produce CAM forms of these receptors and test antipsychotic drugs for inverse agonist activity at these receptors; 3) we will examine effects of constitutive activation on clozapine-sensitive 5HT receptor cellular trafficking, and the effects of inverse agonists on the trafficking of the mutated receptors. The results of these studies should reveal the role inverse agonist activity of antipsychotic drugs plays in the atypical properties of clozapine, and may indicate a major role for one or more of the clozapine-sensitive receptors in the atypical properties of clozapine. This information should be very helpful in designing a new generation of atypical antipsychotic drugs sharing clozapine's unique antipsychotic properties, but lacking its deleterious hematological effects. Information concerning alterations in cellular processing of CAM receptors should also be forthcoming, including information on the molecular domains involved in directing cellular compartmentalization, believed to play a key role in cellular receptor sensitivity states.

描述（由申请人提供）：我们已经证明，氯氮平和 利培酮是一种非典型抗精神病药物， 大鼠5SHT 2A的组成型激活突变体（CAM）形式的特性， 5 HT 2C受体。反向激动剂活性可能是 抗精神病药物，鉴于修改后的三元复合物模型的G蛋白 偶联受体（GPCR），它预测稳态水平的激活， 受体在缺乏配体刺激。进一步研究 抗精神病药物对氯氮平敏感的人SHT的CAM形式的作用 受体是必要的，以确定反向激动剂活性是否是关键 非典型抗精神病药物的性质。为了将研究扩展到 我们已经尝试制备人5 HT 6和5 HT 7受体的CAM形式 通过突变GPCR组成型的两个有充分证据的区域， 活动涉及这些区域突变的初步实验已经产生了 受体的形式要么缺乏稳健的组成型活性，要么产生 显然无效突变形式的受体（5 HT 6）。虽然这些结果 确定抗精神病药的反向激动剂活性的进展缓慢 它们开辟了有趣的研究途径， GPCR家族内和5 HT受体内的结构变异性， 特别的。 因此，我们建议追求三个具体目标：1）我们将继续测试 典型和非典型抗精神病药物对人CAM形式的5 HT 2A和 5 HT 2C受体; 2）我们将继续突变人5 HT 6和5 HT 7 受体产生CAM形式的这些受体和测试抗精神病药物 对于这些受体的反向激动剂活性; 3）我们将检查 氯氮平敏感性5 HT受体细胞的组成性激活 贩运，以及反向激动剂对贩运的影响。 变异受体这些研究的结果应该揭示出 抗精神病药物的激动剂活性在以下非典型性质中起作用： 氯氮平，并可能表明一个或多个的主要作用， 氯氮平的非典型性质中的氯氮平敏感受体。这 信息应该非常有助于设计新一代的非典型 抗精神病药物共享氯氮平独特的抗精神病特性，但 没有有害的血液学效应资料 CAM受体的细胞加工的改变也应该即将到来， 包括参与指导细胞内 区室化，被认为在细胞受体中起关键作用， 敏感国家。