Gabapentin inhibits the activity of the rat excitatory glutamate transporter 3 expressed in Xenopus oocytes

Yang Sook Gil, Jong Hak Kim, Chi Hyo Kim, Jong In Han, Zhiyi Zuo, Hee Jung Baik

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Gabapentin, a derivative of γ-aminobutyric acid (GABA), is used to treat epilepsy and neuropathic pain. The pharmacological mechanisms for gabapentin effects are not completely elucidated. We investigated the effect of gabapentin on the activity of excitatory amino acid transporter 3 (EAAT3) that can regulate extracellular glutamate concentrations. EAAT3 was expressed in Xenopus oocytes. Membrane currents were recorded after application of l-glutamate in the presence or absence of different concentrations of gabapentin (1-300 μM) by using a two-electrode voltage clamp. To determine the effect of gabapentin on Vmax and Km of EAAT3 for l-glutamate, l-glutamate at 3-300 μM was used. To study the effects of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) on gabapentin-induced changes in EAAT3 activity, oocytes were incubated with the PKC activator (Phorbol 12-myristate 13-acetate, PMA), the PKC inhibitors (chelerythrine or staurosporine), and the PI3K inhibitor wortmannin. Gabapentin decreased EAAT3 activity in a concentration-dependent manner and EAAT3 activity was significantly inhibited by 10-300 μM gabapentin. Gabapentin significantly decreased Vmax without affecting Km. PMA increased EAAT3 activity; however, gabapentin attenuated the PMA-induced increase in EAAT3 activity. Pre-incubation of oocytes with chelerythrine, staurosporine, or wortmannin decreased basal EAAT3 activity, which was further reduced by gabapentin. We conclude that gabapentin decreases EAAT3 activity at clinically relevant and higher concentrations, in which PKC and PI3K may not be involved. The results suggest that EAAT3 might not be a target for the anticonvulsant action of gabapentin.

Original languageEnglish
Pages (from-to)112-117
Number of pages6
JournalEuropean Journal of Pharmacology
Volume762
DOIs
StatePublished - 30 May 2015

Keywords

  • <inf>L</inf>-glutamate (PubChem CID: 33032)
  • Chelerythrine (PubChem CID: 2703)
  • Chemical compounds studied in this article Gabapentin (PubChem CID: 3446)
  • Phorbol 12-myristate 13-acetate (PubChem CID: 27924)
  • Staurosporine (PubChem CID: 44259)
  • Wortmannin (PubChem CID: 312145)

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