Structural basis of GABA reuptake inhibition.

ABSTRACT: γ-Aminobutyric acid (GABA) transporter 1 (GAT1)¹ regulates neuronal excitation of the central nervous system by clearing the synaptic cleft of the inhibitory neurotransmitter GABA upon its release from synaptic vesicles. Elevating the levels of GABA in the synaptic cleft, by inhibiting GABA reuptake transporters, is an established strategy to treat neurological disorders, such as epilepsy². Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine³, with an ordered part of only 60 kDa. Our structure reveals that tiagabine locks GAT1 in the inward-open conformation, by blocking the intracellular gate of the GABA release pathway, and thus suppresses neurotransmitter u

SUBMITTER: Motiwala Z 

PROVIDER: S-EPMC9394549 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature