Gabapentin inhibits the activity of the rat excitatory glutamate transporter 3 expressed in Xenopus oocytes
- 주제(키워드) <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)
- 등재 SCIE, SCOPUS
- 발행기관 Elsevier
- 발행년도 2015
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000117773
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.ejphar.2015.05.038
- 저작권 이화여자대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
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 V<inf>max</inf> and K<inf>m</inf> 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 V<inf>max</inf> without affecting K<inf>m</inf>. 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. © 2015 Elsevier B.V. All rights reserved.
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