更新于：2024-05-01

VMAT1

solute carrier family 18 member A1

更新于：2024-05-01

基本信息

别名

CGAT、Chromaffin granule amine transporter、SLC18A1

+ [6]

简介

Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to accumulate high concentrations of monoamines inside the vesicles prior to their release via exocytosis. Transports catecholamines and indolamines with higher affinity for serotonin (PubMed:23337945, PubMed:8643547, PubMed:16326835). Regulates the transvesicular monoaminergic gradient that determines the quantal size. Mediates presynaptic monoaminergic vesicle transport in the amygdala and prefrontal brain regions related with emotion processing in response to environmental stimuli (PubMed:23337945). Unable to uptake serotonin.

关联

项与 VMAT1 相关的药物

Reserpine

利血平

靶点

VMAT1 x VMAT2

作用机制

VMAT1拮抗剂 [+1]

在研机构-

原研机构

Sandoz, Inc.

在研适应症

高血压

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期1955-08-12

Hydrochlorothiazide/Dihydralazine Sulfate/Promethazine Hydrochloride/Rutin/Chloroquine Phosphate/Potassium Chloride/Pyridoxine Hydrochloride/Thiamine Hydrochloride/Reserpine/Magnesium Trisilicate

氢氯噻嗪/硫酸双肼屈嗪/盐酸异丙嗪/芦丁/磷酸氯喹/氯化钾/维生素B6/维生素B1/利血平/三硅酸镁

靶点

H1 receptor x NCC x VMAT1 x VMAT2

作用机制

H1 receptor拮抗剂 [+3]

在研机构-

原研机构-

在研适应症

高血压

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区-

首次获批日期1800-01-20

HG-1098

靶点

VMAT1 x Vesicular transporter

作用机制

VMAT1调节剂 [+1]

在研机构-

原研机构

Human Genome Sciences, Inc.

在研适应症-

非在研适应症

神经系统疾病

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 VMAT1 相关的临床试验

NCT06199778 / TerminatedN/AIIT

A Randomized Controlled Study to Explore the Effect of Intermittent Oro-esophageal Tube Feeding on Severe Traumatic Brain Injury Patients With Tracheostomy

This was a multicenter randomized controlled study of 98 severe Traumatic Brain Injury patients with tracheostomy. Patients enrolled were divided randomly into the observation group with Intermittent Oro-esophageal Tube Feeding (n=50) or the control group with Nasogastric tube feeding (n=48) for enteral nutrition support, respectively. Nutritional status, complications, decannulation of tracheostomy tubes and level of consciousness on day 1 and day 28 were recorded and compared.

开始日期2022-06-01

申办/合作机构

郑州大学

NCT02684786 / Withdrawn临床1期

A Phase I Study of Stellate Ganglion Block and / or Reserpine in Group 2 Pulmonary Hypertension

Pulmonary hypertension Group 2 (PH 2) associated with left-sided heart disease is relatively common, is associated with a poor prognosis, and unfortunately there are no proven medical treatments beyond attempts at correcting the left sided heart disease. Many PH 2 patients have evidence of active constriction of blood vessels from increased nerve traffic. Use of agents or procedures which produce a reversible chemical blockage of this nerve traffic have not been systematically tested in PH 2. The investigators will test whether acute interruption of sympathetic nervous system tone, which local anesthetic block of the stellate ganglion in the neck, will improve PH2, and also test whether the high blood pressure drug reserpine, which blocks sympathetic nerve activity, will do so during a one month trial period.

开始日期2016-07-01

申办/合作机构

Mayo Clinic

NCT03223272 / Completed临床2期IIT

Mechanisms of Refractory Hypertension (Reserpine)

The study is deigned to determine if refractory hypertension is attributable to heightened sympathetic tone by quantifying the antihypertensive benefit of reserpine, a sympatholytic agent, in patients failing other classes of antihypertensive agents.

开始日期2015-07-23

申办/合作机构

The University of Alabama at Birmingham

100 项与 VMAT1 相关的临床结果

登录后查看更多信息

100 项与 VMAT1 相关的转化医学

登录后查看更多信息

0 项与 VMAT1 相关的专利（医药）

登录后查看更多信息

187

项与 VMAT1 相关的文献（医药）

2024-01-02·Journal of inherited metabolic disease

Mouse models for inherited monoamine neurotransmitter disorders.

Article

作者: B Thöny ; J Ng ; M A Kurian ; P Mills ; A Martinez

Several mouse models have been developed to study human defects of primary and secondary inherited monoamine neurotransmitter disorders (iMND). As the field continues to expand, current defects in corresponding mouse models include enzymes and a molecular co-chaperone involved in monoamine synthesis and metabolism (PAH, TH, PITX3, AADC, DBH, MAOA, DNAJC6), tetrahydrobiopterin (BH₄ ) cofactor synthesis and recycling (adGTPCH1/DRD, arGTPCH1, PTPS, SR, DHPR), and vitamin B₆ cofactor deficiency (ALDH7A1), as well as defective monoamine neurotransmitter packaging (VMAT1, VMAT2) and reuptake (DAT). No mouse models are available for human DNAJC12 co-chaperone and PNPO-B₆ deficiencies, disorders associated with recessive variants that result in decreased stability and function of the aromatic amino acid hydroxylases and decreased neurotransmitter synthesis, respectively. More than one mutant mouse is available for some of these defects, which is invaluable as different variant-specific (knock-in) models may provide more insights into underlying mechanisms of disorders, while complete gene inactivation (knock-out) models often have limitations in terms of recapitulating complex human diseases. While these mouse models have common phenotypic traits also observed in patients, reflecting the defective homeostasis of the monoamine neurotransmitter pathways, they also present with disease-specific manifestations with toxic accumulation or deficiency of specific metabolites related to the specific gene affected. This review provides an overview of the currently available models and may give directions toward selecting existing models or generating new ones to investigate novel pathogenic mechanisms and precision therapies.

2023-01-28·BMC genomics

Whole genome sequencing revealed genetic diversity, population structure, and selective signature of Panou Tibetan sheep.

Article

作者: Huibin Shi ; Taotao Li ; Manchun Su ; Huihui Wang ; Qiao Li ; Xia Lang ; Youji Ma

BACKGROUND:

The detection of selective traits in different populations can not only reveal current mechanisms of artificial selection for breeding, but also provide new insights into phenotypic variation in new varieties and the search for genes associated with important traits. Panou sheep is a cultivated breed of Tibetan sheep in China with stable genetic performance, consistent appearance and fast growth and development after decades of artificial selection and cultivation. Due to long-term adaptation to the high altitude, cold and hypoxic environment in the plateau area, they may have formed a unique gene pool that is different from other Tibetan sheep breeds. To explore the genetic resources of Panou sheep, we used next-generation sequencing technology for the first time to investigate the genome-wide population structure, genetic diversity, and candidate signatures of positive selection in Panou sheep.

RESULTS:

Comparative genomic analysis with the closely related species Oula sheep (a native breed of Tibetan sheep in China) was used to screen the population selection signal of Panou sheep. Principal component analysis and neighbor joining tree showed that Panou sheep and Oula sheep had differences in population differentiation. Furthermore, analyses of population structure, they came from the same ancestor, and when K = 2, the two populations could be distinguished. Panou sheep exhibit genetic diversity comparable to Oula sheep, as shown by observed heterozygosity, expected heterozygosity and runs of homozygosity. Genome-wide scanning using the Fst and π ratio methods revealed a list of potentially selected related genes in Panou sheep compared to Oula sheep, including histone deacetylase 9 (HDAC9), protein tyrosine kinase 2 (PTK2), microphthalmia-related transcription factor (MITF), vesicular amine transporter 1 (VAT1), trichohyalin-like 1 (TCHHL1), amine oxidase, copper containing 3 (AOC3), interferon-inducible protein 35 (IFI35).

CONCLUSIONS:

The results suggest that traits related to growth and development and plateau adaptation may be selection targets for the domestication and breeding improvement of Tibetan sheep. This study provides the fundamental footprints for Panou sheep breeding and management.

2023-01-01·Frontiers in endocrinology

Restricted effects of androgens on glucocorticoid signaling in the mouse prefrontal cortex and midbrain.

Article

作者: Jorge Miguel Amaya ; Hetty C M Sips ; Eva M G Viho ; Jan Kroon ; Onno C Meijer

Glucocorticoids are key executors of the physiological response to stress. Previous studies in mice showed that the androgen receptor (AR) influenced the transcriptional outcome of glucocorticoid treatment in white and brown adipocytes and in the liver. In the brain, we observed that chronic hypercorticism induced changes in gene expression that tended to be more pronounced in male mice. In the present study, we investigated if glucocorticoid signaling in the brain could be modulated by androgen. After chronic treatment with corticosterone, dihydrotestosterone, a combination of both, and corticosterone in combination with the AR antagonist enzalutamide, we compared the expression of glucocorticoid receptor (NR3C1, also abbreviated GR) target genes in brain regions where AR and GR are co-expressed, namely: prefrontal cortex, hypothalamus, hippocampus, ventral tegmental area and substantia nigra. We observed that androgen affected glucocorticoid signaling only in the prefrontal cortex and the substantia nigra. Dihydrotestosterone and corticosterone independently and inversely regulated expression of Sgk1 and Tsc22d3 in prefrontal cortex. AR antagonism with enzalutamide attenuated corticosterone-induced expression of Fkbp5 in the prefrontal cortex and of Fkbp5 and Sgk1 in the substantia nigra. Additionally, in the substantia nigra, AR antagonism increased expression of Th and Slc18a1, two genes coding for key components of the dopaminergic system. Our data indicate that androgen influence over glucocorticoid stimulation in the brain is not a dominant phenomenon in the context of high corticosterone levels, but can occur in the prefrontal cortex and substantia nigra.

项与 VMAT1 相关的新闻（医药）

2023-11-08

·生物谷

Nature | 科学家成功揭示神经递质转运蛋白的精细化结构

神经元能通过一种称之为神经递质的化学信号来彼此交流沟通，近日，一篇发表在国际杂志Nature上题为“Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2“的研究报告中，来自美国圣犹大儿童研究医院等机构的科学家们通过研究利用结构生物学知识确定了囊泡单胺转运体2(VMAT 2，vesicular monoamine transporter 2)的结构，其是神经元通信的关键组成部分。通过在不同状态下观察VMAT2，科学家们就能更好的理解其是如何发挥功能的，以及蛋白质的不同形状如何影响药物的结合，这或许是治疗诸如小儿多发性抽动症（Tourette syndrome）等多动症疾病（过度运动）的药物开发的关键信息。单胺类化合物包括多巴胺、血清素和肾上腺素，其在神经元交流沟通中扮演着关键角色，这些分子影响着大脑的工作方式，控制机体的情绪、睡眠、运动、呼吸、循环和多种其它功能；单胺类是由是神经元所释放的神经递质（信号分子），但在其被释放之前必须首先被包装成为囊泡结构。当神经递质被从突触（化学信号从一个神经元传递到另一个神经元的连接处）释放之前，囊泡就是储存神经递质的细胞区室，我们可以将囊泡想象成为神经元细胞的货船，神经化学物质能被包裹在其中，并被带到其需要去的地方。VMATs就是这些囊泡膜上的蛋白质，其能将单胺类化学物移动到其中的空间，就像货船上的装载起重机一样。研究者Chia-Hsueh Lee解释道，VMATs是将这些单胺类神经递质包装到突触囊泡中所需要的转运蛋白；一旦VMAT利用单胺类填充了囊泡，“货船”就会向突触间隙（神经元之间的空间）所移动，并在那里释放化合物。VMAT有两种类型，即VMAT1和VMAT2，VMAT1更加专业，其仅在神经内分泌细胞中存在，而VMAT2则在整个神经系统中都能被发现，且具有重要的临床意义。我们都知道VMAT2在生理学上非常重要，这种转运蛋白是用作治疗诸如舞蹈病和小儿多发性抽动症等多动症药理学相关药物的作用靶点。尽管其非常重要，但VMAT2的结构仍然难以捉摸，这或许就能促使研究人员调查其是如何发挥作用的。如今研究者Lee等人利用冷冻电镜技术获得了VMAT2与单胺血清素以及药物四苯喹嗪（tetrabenazine）和利血平（reserpine）结合的结构，四苯喹嗪和利血平两种药物能分别用来治疗舞蹈病和高血压。科学家成功揭示神经递质转运蛋白的精细化结构。图片来源：Nature (2023). DOI:10.1038/s41586-023-06727-9研究者Yaxin Dai表示，VMAT2是一种小型的膜蛋白，这或许就使其成为了低温电镜结构测定的一个非常具有挑战性的靶点。尽管研究人员所面临的困难重重，但他们使用了一些小技巧，最终捕获了VMAT2的多个结构，这或许就能使其梳理出蛋白质的结构并研究这些药物的确切工作原理。VMAT转运蛋白在运输底物时能采用多种构象（形状），这种模式被称之为交替进入运输，其中蛋白质要么向外，要么向内；为了在原子水平上完全获得机制性的理解，研究人员就需要捕获这种转运蛋白的多个构象结构。研究人员还发现，这种动态机制就意味着药物有多重结合机会，这就证实了药物四苯喹嗪和利血平能结合两种不同的VMAT2构象。30或40年的药理学研究表明，这两种药物能以不同的方式来结合转运蛋白，但并没有人知道其在原子细节上是如何发挥作用的，而研究人员所发现的结构就很好地阐明了这两种药物能稳定转运蛋白的两种不同构象，从而阻断其活性表现。VMAT2与血清素结合的结构就能促使研究人员确定能与神经递质相互作用并驱动其转运的特定氨基酸，研究人员相信这是一种共同的机制，这种转运蛋白或能利用这一机制来参与到所有单胺化合物的作用中来。尽管这项研究为理解单胺的转运提供了一定的帮助，但研究人员Lee等人还想继续深入理解其中的分子机制，比如，单胺类进入囊泡是质子向另一个方向运动而产生的。研究者Lee说道，我们识别出了对质子依赖过程很重要的氨基酸，但我们仍然并不知道质子驱动这种转运过程的分子机制，确定这一机制就是我们未来的研究方向，有助于研究人员更充分地理解这种转运蛋白的作用机制。原始出处：Shabareesh Pidathala,Shuyun Liao,Yaxin Dai, et al. Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2, Nature (2023). DOI:10.1038/s41586-023-06727-9本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

临床1期

2023-11-06

·药明康德

疗效持续维持达50周！口服小分子3期试验积极，显著改善亨廷顿病症状

Neurocrine Biosciences日前公布KINECT-HD2临床3期研究的中期结果，该研究评估Ingrezza（valbenazine）胶囊作为亨廷顿病（HD）相关舞蹈病成人患者长期治疗选择的作用。初步数据表明，早在第2周时每日一次Ingrezza胶囊给药即改善患者的舞蹈病症状，该获益持续至第50周。 KINECT-HD2的中期分析显示，在初始剂量40 mg下，Ingrezza在第2周起表现出疗效，并在高达80 mg的剂量下维持其疗效至第50周（参见下图）。相当大比例的受试者（60.9%）及其临床医生（58.9%）报告，到第6周时症状状态“改善”或“极大改善”。到第50周，这些数值进一步增加，约四分之三的受试者（74.2%）和研究人员（76.9%）报告症状显著改善。本试验中显示的安全性特征与既往结果一致。最常见治疗相关不良事件包括跌倒（30.4%）、疲乏（24.0%）和嗜睡（24.0%）。 Ingrezza是一款选择性囊泡单胺转运体2（VMAT2）抑制剂，对VMAT1、多巴胺能、5-羟色胺能、肾上腺素能、组胺能或毒蕈碱受体无明显亲和力。Ingrezza通过选择性靶向VMAT2，被认为可减少额外的多巴胺信号，这可能导致不可控运动的减少。Ingrezza已获FDA批准用于治疗成人亨廷顿病患者的迟发性运动障碍，并可与大多数精神科药物（如抗精神病药或抗抑郁药）联合使用。今年8月，Ingrezza获FDA批准用于治疗亨廷顿病相关舞蹈病成人患者。参考资料：[1] Neurocrine Biosciences® Presents INGREZZA® (valbenazine) Capsules Interim Data Demonstrating Sustained Improvements in Chorea Associated With Huntington's Disease Through Week 50 at Huntington Study Group 2023. Retrieved November 3, 2023 from https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciencesr-presents-ingrezzar-valbenazine-capsules 内容来源于网络，如有侵权，请联系删除。

基因疗法临床结果

2023-11-02

·生物谷

Nature | 张哲/李佳学共同揭示囊泡单胺转运蛋白VMAT2的药物抑制及底物转运机制

单胺类化合物，如多巴胺、5-羟色胺、去甲肾上腺素、肾上腺素和组胺，是神经系统中重要的神经递质，负责调控多种生理和认知功能，如运动、睡眠、奖赏和情绪等。单胺环路功能异常会引起抑郁症、帕金森氏症和舞蹈症等精神类或神经退行性疾病。囊泡单胺转运蛋白（vesicular monoamine transporters, VMATs）将突触前神经元合成的单胺类化合物转运进分泌囊泡，这是单胺类神经递质向突触间隙有效释放的前提。临床上，VMATs已经被作为高血压、亨廷顿氏舞蹈症等运动障碍、精神性焦虑以及精神性兴奋剂滥用的潜在治疗靶点。哺乳动物中存在两个VMAT家族成员，VMAT1（SLC18A1）和VMAT2（SLC18A2）。VMAT1蛋白仅在外周神经分泌细胞中表达，而VMAT2蛋白则在中枢和外周神经系统中广泛表达并承担主要的囊泡单胺转运功能。因此，VMAT2是目前多种单胺异常相关疾病治疗药物的主要靶点。VMAT2的抑制剂丁苯那嗪（tetrabenazine, TBZ）及其衍生物氘代丁苯那嗪（deutetrabenazine）和缬苯那嗪（valbenazine）已经被FDA批准用于治疗亨廷顿氏舞蹈症或迟发性运动障碍（tardive dyskinesia）；另一个VMAT2的抑制剂利血平（reserpine, RSP）则是最早的交感神经抑制类降压药。此前的研究显示，TBZ及其衍生物和RSP对VMAT2的抑制机制不同：TBZ是非竞争性抑制剂，而RSP是竞争性抑制剂；而且，TBZ特异性抑制VMAT2，而RSP是VMAT1和VMAT2共同的抑制剂。然而，目前VMAT蛋白底物转运和药物作用的分子机制均不明确。2023年11月1日，北京大学生命科学学院张哲课题组和美国圣裘德儿童研究医院李佳学课题组合作在Nature杂志发布了题为“Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2”的研究论文。该工作首次报道了人源VMAT2蛋白结合抑制剂TBZ、RSP及其底物5-羟色胺（5-HT）的冷冻电镜结构，揭示了两种抑制剂发挥功能以及VMAT2转运底物的分子机制（图1）。VMAT2蛋白的分子量仅约56 kDa且缺乏可溶结构域，这对使用冷冻电镜技术进行结构解析提出了巨大的挑战。作者采取融合蛋白的策略，将MBP蛋白刚性融合在VMAT2的N端，同时将与MBP特异性结合的DARPin蛋白融合在VMAT2的C端，从而增大了VMAT2的分子量并提高了蛋白的稳定性，借此获得了VMAT2与几种小分子复合物的高分辨率结构（2.9-3.7 Å）（图1A）。作者首先解析了VMAT2结合TBZ的结构。在该结构中，VMAT2蛋白呈现lumen-facing构象，TBZ的结合将VMAT2进一步锁定在occluded状态，此时VMAT2对膜两侧均不开放，由此阻碍了底物的结合和转运（图1A）。此前的研究表明，VMAT2在cytoplasm-facing构象时与RSP的亲和力较强，为了获得与RSP的复合物结构，作者对VMAT2胞质侧门控处关键氨基酸残基进行了突变，最终解析了VMAT2突变体Y418S在cytoplasm-facing构象下与RSP以及底物5-HT的复合物结构。这两个结构显示，5-HT与RSP结合在VMAT2中的相同位点，由于RSP分子量较大，与VMAT2亲和力较强，因此可以竞争性抑制底物的结合和转运（图1A）。作者进一步通过比较两种不同构象状态的结构变化，提出了VMAT2利用alternating access方式转运底物的工作模型（图1B）。期间，作者利用大量的功能实验验证了VMAT2中的关键氨基酸残基在抑制剂结合和底物转运中的作用，极好地印证了结构方面的分析和发现，并阐明了TBZ特异性抑制VMAT2而非VMAT1的分子机制。总之，这项研究加深了人们对VMAT2及SLC18家族相关囊泡神经递质转运蛋白结构和功能机制的理解，并为针对这些蛋白质的药物研发和改造提供了重要的参考。图1. VMAT2的药物抑制及底物转运机制美国圣裘德儿童研究医院李佳学研究员和北京大学张哲研究员为本文共同通讯作者。美国圣裘德儿童研究医院博士后Shabareesh Pidathala、北京大学前沿交叉学科研究院生命联合中心2020级博士生廖述筠和美国圣裘德儿童研究医院博士后戴亚鑫为本文共同第一作者。美国圣裘德儿童研究医院李肖和张齐伦，以及张哲课题组前技术员龙昌坤对本文做出重要贡献。另外，美国圣裘德儿童研究医院细胞和组织成像中心的工作人员、北京大学生命科学学院郑鹏里研究员及博士生简舒怡也为本研究提供了帮助。本研究得到国家重点研发计划重点专项、国家自然科学基金面上项目、生命科学联合中心、膜生物学国家重点实验室、北京大学生命科学学院启东产业创新基金、李革-赵宁生命科学青年研究基金、National Institutes of Health和ALSAC的资助；并依托北京大学生命科学学院公共仪器中心凤凰工程蛋白质平台的技术支持。原文链接：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41586-023-06727-9本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

临床研究