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，非典型抗精神病药，具有有效的反向激动剂 大鼠 5SHT2A 的组成型激活突变体 (CAM) 形式的特性和 5HT2C受体。反向激动剂活性可能是 抗精神病药物，考虑到修改后的 G 蛋白三元复合物模型 偶联受体（GPCR），它预测激活的稳态水平 受体在没有配体刺激的情况下。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 受体对于确定反向激动剂活性是否是关键是必要的 非典型抗精神病药物的特性。为了将研究范围扩大到 人类 5HT6 和 5HT7 受体，我们尝试将这些受体制成 CAM 形式 通过突变 GPCR 组成型的两个有据可查的区域来实现受体 活动。涉及这些区域突变的初步实验已经产生 受体的形式要么缺乏强大的组成活性，要么产生 受体（5HT6）的明显无效突变形式。虽然这些结果已经 确定抗精神病药反向激动剂活性的进展缓慢 针对这些受体的药物，它们开辟了有趣的研究途径 GPCR 家族和 5HT 受体内结构的变异性 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 5HT2A 和人类 CAM 形式的典型和非典型抗精神病药物 5HT2C受体； 2）我们将继续对人类5HT6和5HT7进行突变 受体产生这些受体的 CAM 形式并测试抗精神病药物 对于这些受体的反向激动剂活性； 3）我们将检查的影响 氯氮平敏感5HT受体细胞的组成型激活 贩运，以及反向激动剂对贩运的影响 突变的受体。这些研究的结果应该揭示逆作用 抗精神病药物的激动剂活性在非典型特性中发挥作用 氯氮平，并且可能表明一种或多种的主要作用 氯氮平的非典型特性中的氯氮平敏感受体。这 这些信息对于设计新一代非典型系统非常有帮助。 抗精神病药物具有氯氮平独特的抗精神病特性，但是 缺乏其有害的血液学影响。有关信息 CAM 受体的细胞加工过程也将发生变化， 包括有关指导细胞的分子域的信息 区室化，被认为在细胞受体中发挥关键作用 敏感状态。