GABA transporter lysine 448: A key residue for tricyclic antidepressants interaction

Francesca Cherubino, Andreea Miszner, Maria Daniela Renna, Rachele Sangaletti, Stefano Giovannardi, Elena Bossi

Research output: Contribution to journalArticlepeer-review

Abstract

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 (γ-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.

Original languageEnglish
Pages (from-to)3797-3808
Number of pages12
JournalCellular and Molecular Life Sciences
Volume66
Issue number23
DOIs
Publication statusPublished - Jan 2009

Keywords

  • Antidepressant
  • Electrophysiology
  • GAT1
  • SLC6A1
  • Uncompetitive inhibition

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Molecular Medicine
  • Pharmacology
  • Cellular and Molecular Neuroscience

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