PSYCHOSTIMULANT RECOGNITION BY SEROTONIN TRANSPORTERS

血清素转运蛋白对精神兴奋剂的识别

• 批准号: 6660359
• 负责人: ERIC L BARKER
• 金额: $ 18.55万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6660359
• 关键词: Xenopus oocyte; amphetamines; antidepressants; cocaine; intermolecular interaction; ligands; neuropharmacology; neurotransmitter agonist; neurotransmitter antagonist; protein structure function; serotonin; serotonin inhibitor; serotonin transporter; site directed mutagenesis

The serotonin transporter (SERT) is the molecular target for most antidepressant drugs as well as many drugs of abuse. Antidepressants such as paroxetine, fluoxetine, and imipramine bind to the transporter and inhibit serotonin uptake, thereby prolonging the extracellular lifespan of the neurotransmitter. The abused psychostimulants cocaine and amphetamine also bind to the transporter, but have distinct pharmacologic effects leading to abuse potential and possible neurotoxicity. Despite the cloning of SERT in the early 1990's, very little information is available regarding the molecular and cellular neurobiology surrounding the function of this transport protein. This project uses a multidisciplinary approach aimed at significantly advancing knowledge regarding the molecular pharmacology of psychostimulants at SERTs. The studies will use multiple techniques including expression and characterization of recombinant transporters in mammalian cells, electrophysiology, immunoblotting, the formation of chimeric proteins, and site- directed mutagenesis to identify amino acids involved with specific transporter functions including antagonist and substrate binding. In addition, computer-assisted structure-activity studies of cocaine and amphetamine derivatives will be coupled with mutagenesis in an attempt to identify direct ligand- transporter interactions. Therefore, the specific aims of this project are 1) to identify transporter domains and residues involved in recognition of SERT antagonists such as cocaine and 2) to determine the contributions of specific SERT domains to substrate properties such as translocation, efflux, and channel- like activity. The proposed strategies will provide critical new information linking protein structure to functional properties of the transporter and an enhanced understanding of the molecular mechanisms of action for psychotherapeutic and abused drugs.

5-羟色胺转运体（SERT）是大多数抗抑郁药物以及许多滥用药物的分子靶点。抗抑郁药如帕罗西汀、氟西汀和丙咪嗪与转运蛋白结合并抑制5-羟色胺摄取，从而延长神经递质的细胞外寿命。滥用的精神兴奋剂可卡因和安非他明也与转运蛋白结合，但具有不同的药理作用，导致滥用潜力和可能的神经毒性。 尽管SERT在20世纪90年代早期被克隆，但是关于围绕这种转运蛋白功能的分子和细胞神经生物学的信息非常少。 该项目采用多学科的方法，旨在显着推进有关SERT精神兴奋剂的分子药理学知识。 这些研究将使用多种技术，包括哺乳动物细胞中重组转运蛋白的表达和表征、电生理学、免疫印迹、嵌合蛋白的形成和定点诱变，以鉴定与特定转运蛋白功能（包括拮抗剂和底物结合）相关的氨基酸。 此外，可卡因和安非他明衍生物的计算机辅助结构-活性研究将与诱变相结合，试图确定直接的配体-转运蛋白相互作用。 因此，本项目的具体目的是1）鉴定参与识别SERT拮抗剂（如可卡因）的转运蛋白结构域和残基，2）确定特定SERT结构域对底物性质（如易位、外排和通道样活性）的贡献。 拟议的战略将提供关键的新信息连接蛋白质结构的转运蛋白的功能特性，并提高对精神治疗和滥用药物的分子作用机制的理解。

项目成果

Early-onset schizophrenia is associated with impaired adolescent development of attentional capacity using the identical pairs continuous performance test.

使用相同配对连续表现测试，早发性精神分裂症与青少年注意力能力发展受损有关。

• DOI: 10.1016/j.schres.2005.09.015
• 发表时间: 2006
• 期刊: Schizophrenia research
• 影响因子: 4.5
• 作者: Thaden,Emily;Rhinewine,JosephP;Lencz,Todd;Kester,Hana;Cervellione,KellyL;Henderson,Inika;Roofeh,David;Burdick,KatherineE;Napolitano,Barbara;Cornblatt,BarbaraA;Kumra,Sanjiv
• 通讯作者: Kumra,Sanjiv

GRASPing for consensus about the Golgi apparatus.

• DOI: 10.1083/jcb.202103117
• 发表时间: 2021-05-03
• 期刊: The Journal of cell biology
• 作者: Burd CG