Jonas S Mortensen, Amalie N L Mikkelsen, Petrine Wellendorph
{"title":"调节 GABA 转运体以治疗神经系统疾病的方法。","authors":"Jonas S Mortensen, Amalie N L Mikkelsen, Petrine Wellendorph","doi":"10.1080/14728222.2024.2383611","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>The main inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), is involved in a multitude of neurological and psychiatric disorders characterized by an imbalance in excitatory and inhibitory signaling. Regulation of extracellular levels of GABA is maintained by the four GABA transporters (GATs; GAT1, GAT2, GAT3, and BGT1), Na<sup>+</sup>/Cl<sup>-</sup>-coupled transporters of the solute carrier 6 (SLC6) family. Despite mounting evidence for the involvement of the non-GAT1 GABA transporters in diseases, only GAT1 has successfully been translated into clinical practice via the drug tiagabine.</p><p><strong>Areas covered: </strong>In this review, all four GATs will be described in terms of their involvement in disease, and the most recent data on structure, function, expression, and localization discussed in relation to their potential role as drug targets. This includes an overview of various ways to modulate the GATs in relation to treatment of diseases caused by imbalances in the GABAergic system.</p><p><strong>Expert opinion: </strong>The recent publication of various GAT1 structures is an important milestone for future development of compounds targeting the GATs. Such information can provide much needed insight into mechanistic aspects of all GAT subtypes and be utilized to design improved ligands for this highly interesting drug target class.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"529-543"},"PeriodicalIF":4.6000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Ways of modulating GABA transporters to treat neurological disease.\",\"authors\":\"Jonas S Mortensen, Amalie N L Mikkelsen, Petrine Wellendorph\",\"doi\":\"10.1080/14728222.2024.2383611\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>The main inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), is involved in a multitude of neurological and psychiatric disorders characterized by an imbalance in excitatory and inhibitory signaling. Regulation of extracellular levels of GABA is maintained by the four GABA transporters (GATs; GAT1, GAT2, GAT3, and BGT1), Na<sup>+</sup>/Cl<sup>-</sup>-coupled transporters of the solute carrier 6 (SLC6) family. Despite mounting evidence for the involvement of the non-GAT1 GABA transporters in diseases, only GAT1 has successfully been translated into clinical practice via the drug tiagabine.</p><p><strong>Areas covered: </strong>In this review, all four GATs will be described in terms of their involvement in disease, and the most recent data on structure, function, expression, and localization discussed in relation to their potential role as drug targets. This includes an overview of various ways to modulate the GATs in relation to treatment of diseases caused by imbalances in the GABAergic system.</p><p><strong>Expert opinion: </strong>The recent publication of various GAT1 structures is an important milestone for future development of compounds targeting the GATs. Such information can provide much needed insight into mechanistic aspects of all GAT subtypes and be utilized to design improved ligands for this highly interesting drug target class.</p>\",\"PeriodicalId\":12185,\"journal\":{\"name\":\"Expert Opinion on Therapeutic Targets\",\"volume\":\" \",\"pages\":\"529-543\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Expert Opinion on Therapeutic Targets\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14728222.2024.2383611\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Expert Opinion on Therapeutic Targets","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14728222.2024.2383611","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/27 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Ways of modulating GABA transporters to treat neurological disease.
Introduction: The main inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), is involved in a multitude of neurological and psychiatric disorders characterized by an imbalance in excitatory and inhibitory signaling. Regulation of extracellular levels of GABA is maintained by the four GABA transporters (GATs; GAT1, GAT2, GAT3, and BGT1), Na+/Cl--coupled transporters of the solute carrier 6 (SLC6) family. Despite mounting evidence for the involvement of the non-GAT1 GABA transporters in diseases, only GAT1 has successfully been translated into clinical practice via the drug tiagabine.
Areas covered: In this review, all four GATs will be described in terms of their involvement in disease, and the most recent data on structure, function, expression, and localization discussed in relation to their potential role as drug targets. This includes an overview of various ways to modulate the GATs in relation to treatment of diseases caused by imbalances in the GABAergic system.
Expert opinion: The recent publication of various GAT1 structures is an important milestone for future development of compounds targeting the GATs. Such information can provide much needed insight into mechanistic aspects of all GAT subtypes and be utilized to design improved ligands for this highly interesting drug target class.
期刊介绍:
The journal evaluates molecules, signalling pathways, receptors and other therapeutic targets and their potential as candidates for drug development. Articles in this journal focus on the molecular level and early preclinical studies. Articles should not include clinical information including specific drugs and clinical trials.
The Editors welcome:
Reviews covering novel disease targets at the molecular level and information on early preclinical studies and their implications for future drug development.
Articles should not include clinical information including specific drugs and clinical trials.
Original research papers reporting results of target selection and validation studies and basic mechanism of action studies for investigative and marketed drugs.
The audience consists of scientists, managers and decision makers in the pharmaceutical industry, academic researchers working in the field of molecular medicine and others closely involved in R&D.