Ways of modulating GABA transporters to treat neurological disease

Jonas S. Mortensen*, Amalie N.L. Mikkelsen, Petrine Wellendorph

*Corresponding author for this work

Research output: Contribution to journalReviewResearchpeer-review

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Abstract

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.

Original languageEnglish
JournalExpert Opinion On Therapeutic Targets
Volume28
Issue number7
Pages (from-to)529-543
ISSN1472-8222
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • Drug development
  • epilepsy
  • GABAergic system
  • inhibitory signaling
  • ischemic stroke
  • pharmacochaperones
  • SLC6
  • tonic inhibition

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