GABA transporter lysine 448: a key residue for tricyclic  antidepressants interaction.
The effects of three tricyclic antidepressants (TCAs) and two serotonin selective reuptake inhibitors (SSRIs) have been studied with an electrophysiological approach on Xenopus laevis oocytes expressing the rat GABA (gamma-Aminobutyric-acid) transporter rGAT1. All tested TCAs and SSRIs inhibit the GABA-associated current in a dose-dependent way with low but comparable efficacy. The pre-steady-state and uncoupled currents appear substantially unaffected. The efficacy of desipramine, but not of the other drugs, is strongly increased in the lysine-glutamate or -aspartate mutants K448E and K448D. Comparison of I(max) and K(0.5GABA) in the absence and presence of desipramine showed that both parameters are reduced by the drug in the wild-type and in the K448E mutant. This suggests an uncompetitive inhibition, in which the drug can bind only after the substrate, an explanation in agreement with the lack of effects on the pre-steady-state and leak currents, and with the known structural data.
Cherubino
Francesca
F
Laboratory of Cellular and Molecular Physiology, Department of Biotechnology and Molecular Sciences, University of Insubria, DBSM, Via Dunant 3, 21100 Varese, Italy.
Miszner
Andreea
A
Renna
Maria Daniela
MD
Sangaletti
Rachele
R
Giovannardi
Stefano
S
Bossi
Elena
E
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002460:Cell Line; D004594:Electrophysiology; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020128:Inhibitory Concentration 50; D017354:Point Mutation; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014982:Xenopus laevis
D000929:Antidepressive Agents, Tricyclic; D050485:GABA Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors