Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1 Tat and cocaine

分子机制：HIV-1 Tat 和可卡因导致单胺转运蛋白失调

• 批准号: 10343679
• 负责人: Jay P. McLaughlin
• 金额: $ 51.52万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343679
• 关键词: Affect; Attention; Attenuated; Automobile Driving; Behavioral; Binding; Binding Sites; Biological Assay; Brain; Brain region; Cells; Chemosensitization; Cocaine; Cocaine Abuse; Cognition; Cognitive; Collaborations; Computer Models; Data; Dopamine; Dose; Drug Modulation; Drug usage; Exposure to; Functional disorder; Funding; Genetic Transcription; Goals; Grant; HIV; HIV-1; HIV-associated neurocognitive disorder; Homeostasis; Human; Impairment; In Vitro; Incidence; Individual; Infection; Learning; Life; Link; Measures; Mediating; Memory; Modeling; Molecular; Moods; Motivation; Mus; Neurocognitive; Neurocognitive Deficit; Neurons; Norepinephrine; Pathogenicity; Patients; Performance; Periodicity; Peripheral; Pharmacology; Physiological; Play; Prefrontal Cortex; Prevalence; Proteins; Publishing; Quinazolines; Recombinants; Regulation; Rewards; Risk; Risk Factors; Role; Scanning; Series; Severities; Signal Transduction; Site; Site-Directed Mutagenesis; Synapses; Synaptosomes; System; Testing; Therapeutic; Therapeutic Intervention; Trans-Activators; Transgenic Mice; Transgenic Organisms; Validation; Virus Replication; Work; analog; antiretroviral therapy; behavioral pharmacology; cognitive function; conformational conversion; dopamine system; dopamine transporter; dopaminergic neuron; drug of abuse; drug reward; genetic regulatory protein; improved; inhibitor; molecular dynamics; monoamine; mouse model; mutant; neuropathology; neuropsychiatry; noradrenaline transporter; novel; patch clamp; predictive modeling; protein protein interaction; reuptake; serotonin transporter; transmission process; uptake

Perturbation of dopaminergic transmission is implicated as a risk factor of HIV-1 associated neurocognitive disorders (HAND). Dopaminergic system plays a causal role in drug rewarding and modulation of the brain function including cognition. Prefrontal cortex is an important brain region for higher cognitive function, where norepinephrine transporter (NET) is the primary mechanism of homeostatic regulation of stable synaptic dopaminergic tone. HIV-1 Tat protein and cocaine synergistically increase synaptic dopamine levels, thereby producing neurocognitive impairment. Our initial findings show that in vitro exposure to recombinant Tat1-86 inhibits dopamine and norepinephrine reuptake by dopamine transporter (DAT) and NET and Tat binds to DAT and NET through a direct protein-protein interaction. We have demonstrated that Tat-induced inhibition of DAT function is mediated by binding to allosteric binding site(s) on DAT, not by interacting with the DA uptake site. Accordingly, attenuating Tat binding to DAT would be expected to have minimal influence on physiological DA transport. Indeed, our recent findings show that a novel quinazoline series of allosteric modulators decrease cocaine potency for inhibition of DA uptake and attenuate Tat-induced inhibition of DA reuptake and cocaine binding by DAT. We hypothesize that Tat, via the unique allosteric modulatory sites, perturbs the DAT and NET regulatory network that normally sustains concentrative DA or NE transport and potentiates cocaine’s effect on DAT and NET, resulting in DA/NE-linked neuropsychiatric dysfunction prominently featured in HAND. We will (Aim 1) Identify the binding sites for Tat in human NET, and explore allosteric modulation of this transporter by Tat and cocaine; (Aim 2) determine the pathogenic role of DAT/NET-mediated dopaminergic transmission in inducible Tat transgenic mice by assessment of Fast-scan cyclic voltammetry and whole cell patch clamp recording; and (Aim 3) perform proof of concept studies using novel allosteric modulators to establish their potential for therapeutic application in HAND using integrated computational modeling, pharmacological, and behavioral approaches. Our long-term goal is to explore new ways to target DAT/NET for therapeutic interventions to improve neurocognitive dysfunction of HAND in concurrent cocaine abusers.

多巴胺能传播的扰动被认为是 HIV-1 相关的危险因素 神经认知障碍（HAND）。多巴胺能系统在药物奖赏中起着因果作用。 和调节大脑功能，包括认知。 具有较高认知功能的区域，其中去甲肾上腺素转运蛋白 (NET) 是主要的 稳定突触多巴胺能张力的稳态调节机制。 和可卡因协同增加突触多巴胺水平，从而产生 我们的初步研究结果表明，体外暴露于重组 Tat1-86 会导致神经认知障碍。 抑制多巴胺转运蛋白 (DAT) 和 NET 的多巴胺和去甲肾上腺素再摄取 我们已经证明，Tat 通过直接的蛋白质-蛋白质相互作用与 DAT 和 NET 结合。 Tat 诱导的 DAT 功能抑制是通过与变构结合位点结合介导的 DAT，不通过与 DA 摄取位点相互作用，从而减弱 Tat 与 DAT 的结合。 事实上，我们最近的研究预计对生理 DA 运输影响最小。 研究结果表明，新型喹唑啉系列变构调节剂可降低可卡因的效力 用于抑制 DA 摄取并减弱 Tat 诱导的 DA 再摄取和可卡因抑制 我们勇敢地说，Tat 通过独特的变构调节位点来扰乱。 通常维持集中 DA 或 NE 传输的 DAT 和 NET 监管网络 并增强可卡因对 DAT 和 NET 的影响，导致 DA/NE 相关的神经精神疾病 HAND 中突出的功能障碍我们将（目标 1）识别 Tat 的结合位点。 human NET，并探索 Tat 和可卡因对该转运蛋白的变构调节（目标 2）； 确定 DAT/NET 介导的多巴胺能传递在诱导型 Tat 中的致病作用 通过快速扫描循环伏安法和全细胞膜片钳评估转基因小鼠 记录；和（目标 3）使用新型变构调节剂进行概念验证研究 使用集成计算确定其在 HAND 中的治疗应用潜力 我们的长期目标是探索新的建模、药理学和行为方法。 以 DAT/NET 为目标进行治疗干预以改善神经认知功能障碍的方法 向并发可卡因滥用者伸出援手。

项目成果

Synthesis and biological evaluation of ranitidine analogs as multiple-target-directed cognitive enhancers for the treatment of Alzheimer's disease.

雷尼替丁类似物作为多靶点定向认知增强剂用于治疗阿尔茨海默病的合成和生物学评价。

• 发表时间: 2016-11-15
• 影响因子: 2.7
• 作者: Gao, Jie;Midde, Narasimha;Zhu, Jun;Terry, Alvin V;McInnes, Campbell;Chapman, James M
• 通讯作者: Chapman, James M

Viral mechanisms: Tat modulates DAT.

病毒机制：Tat 调节 DAT。

• 发表时间: 2015-04
• 影响因子: 14.8
• 作者: Bucci; Mirella
• 通讯作者: Mirella

SRI-32743, a novel allosteric modulator, attenuates HIV-1 Tat protein-induced inhibition of the dopamine transporter and alleviates the potentiation of cocaine reward in HIV-1 Tat transgenic mice.

SRI-32743 是一种新型变构调节剂，可减弱 HIV-1 Tat 蛋白诱导的多巴胺转运蛋白抑制，并减轻 HIV-1 Tat 转基因小鼠中可卡因奖赏的增强。

• 发表时间: 2022-12-01
• 影响因子: 4.7
• 作者: Zhu, Jun;Quizon, Pamela M;Wang, Yingying;Adeniran, Charles A;Strauss, Matthew J;Jiménez;Patel, Palak;Cirino, Thomas J;Eans, Shainnel O;Hammond, Haylee R;Deliscar, Laure S;O'Hara, Priscilla;Saini, Surendra K;Ofori, Edward;Vekari
• 通讯作者: Vekari

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects.

分子机制：ERK 信号传导、药物成瘾和行为影响。

• DOI: 10.1016/bs.pmbts.2015.10.017
• 发表时间: 2016
• 期刊: Progress in molecular biology and translational science
• 作者: Sun WL;Quizon PM;Zhu J
• 通讯作者: Zhu J