Inhibition of sigma-1 receptors substantially modulates GABA and glutamate transport in presynaptic nerve terminals

Natalia Pozdnyakova, Natalia Krisanova, Marina Dudarenko, Edijs Vavers, Liga Zvejniece, Maija Dambrova, Tatiana Borisova

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric disorders and are a novel target for the treatment of such disorders. Sig-1R expression/activity deficits are linked to neurodegeneration, whereas the mechanisms mediated by Sig-1R are still unclear. Here, presynaptic [3H]GABA and L-[14C]glutamate transport was analysed in rat brain nerve terminals (synaptosomes) in the presence of the Sig-1R antagonist NE-100. NE-100 at doses of 1 and 10 μM increased the initial rate of synaptosomal [3H]GABA uptake, whereas 50 and 100 μM NE-100 decreased this rate, exerting a biphasic mode of action.Antagonists of GABAA and GABAB receptors, flumazenil and saclofen, respectively, prevented an increase in [3H]GABA uptake caused by 10 μM NE-100. L-[14C]glutamate uptake was decreased by 10–100 μM NE-100. A decrease in the uptake of both neurotransmitters mediated by NE-100 (50–100 μM) may have resulted from simultaneous antagonist-induced membrane depolarization, which was measured using the potential-sensitive fluorescent dye rhodamine 6G. The extracellular level of [3H]GABA was decreased by 1–10 μM NE-100, but that of L-[14C]glutamate remained unchanged. The tonic release of [3H]GABA measured in the presence of NO-711 was not changed by the antagonist, suggesting that NE-100 did not disrupt membrane integrity. The KCl- and FCCP-induced transporter-mediated release of L-[14C]glutamate was decreased by the antagonist; this may underlie the neuroprotective action of the antagonist in hypoxia/ischaemia. NE-100 (10–100 μM) decreased the KCl-evoked exocytotic release of [3H]GABA and L-[14C]glutamate, whereas the induction of the release of both neurotransmitters by the Ca2+ ionophore ionomycin was not affected by the antagonist; therefore, the mitigation of KCl-evoked exocytosis was associated with the NE-100-induced dysfunction of potential-dependent Ca2+ channels. Therefore, the Sig-1R antagonist can specifically act in an acute manner at the presynaptic level through the modulation of GABA and glutamate uptake, transporter-mediated release and exocytosis.

Original languageEnglish
Article number113434
JournalExperimental Neurology
Volume333
DOIs
Publication statusPublished - Nov 2020
Externally publishedYes

Keywords

  • Antagonist NE-100
  • Brain nerve terminals
  • Exocytosis
  • Extracellular level
  • GABA
  • Glutamate
  • Sigma-1 receptors
  • Transporter-mediated uptake/release

Field of Science

  • 3.1 Basic medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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