Internal gate mutants of the GABA transporter GAT1 are capable of substrate exchange

Neuropharmacology
Oshrat Dayan-Alon, Baruch I Kanner

Abstract

GAT1 is a member of the neurotransmitter:sodium: symporter family and mediates transport of GABA together with sodium and chloride in an electrogenic process enabling efficient synaptic transmission. Biochemical and modelling studies based on the structure of the bacterial homologue LeuT are consistent with a transport mechanism whereby the binding pocket is alternately accessible to either side of the membrane. This is achieved by the sequential opening and closing of extracellular and intracellular gates. The amino acid residues participating in the formation of these gates are highly conserved within the neurotransmitter:sodium: symporter family. Net flux requires that the gating mechanism is operative regardless if the binding pocket is loaded with substrate or empty. On the other hand, exchange of labelled for non-labelled substrate across the membrane only requires gating in the presence of substrate. To address the question if the gating requirements of the substrate-bound and empty transporters are similar or different, we analyzed the impact of mutation of intra- and extra-cellular gate residues on net GABA influx and on exchange by liposomes inlaid with the mutant transporters. Whereas net flux by all four internal ga...Continue Reading

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Citations

Apr 28, 2021·Neurochemical Research·Niels Christian DanboltYun Zhou
Aug 5, 2021·Neurochemical Research·Solveig G SchmidtClaus J Loland

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