Heblich Fay, Tran Van Minh Alexandra, Hendrich Jan, Watschinger Katrin, Dolphin Annette C
Laboratory of Cellular and Molecular Neuroscience, Department of Pharmacology, University College London, London, United Kingdom.
Channels (Austin). 2008 Jan-Feb;2(1):4-9. doi: 10.4161/chan.2.1.6045. Epub 2008 Apr 4.
The mechanism of action of gabapentin is still not well understood. It binds to the alpha(2)delta-1 and alpha(2)delta-2 subunits of voltage-gated calcium channels but has little acute effect on calcium currents in several systems. However, our recent results conclusively demonstrated that gabapentin inhibited calcium currents when applied chronically but not acutely, both in heterologous expression systems and in dorsal root ganglion neurons.(1) In that study we only examined a 40-hour time point of incubation with gabapentin, and here we have extended these results to include the effect of up to 6 and 20 hours incubation with gabapentin on calcium channel currents formed from Ca(V)2.1/beta(4)/alpha(2)delta-2 subunits. Gabapentin was significantly effective to inhibit the currents if included for 17-20 hours prior to recording, but it did not produce a significant inhibition if included for 3-6 hours. We previously concluded that gabapentin acts primarily at an intracellular location, requiring uptake into cells. However, this effect is mediated by alpha(2)delta subunits, being prevented by mutations in either alpha(2)delta-1 or alpha(2)delta-2 that abolish gabapentin binding.(1) Furthermore, we also showed that the trafficking of alpha(2)delta-2 and Ca(V)2 channels was disrupted by gabapentin. Here we have also extended that study, to show that the cell-surface expression of Ca(V)2.1 is not reduced by chronic gabapentin if it is co-expressed with alpha(2)delta-2 containing a point mutation (R282A) that prevents gabapentin binding.
加巴喷丁的作用机制仍未完全明确。它与电压门控钙通道的α(2)δ-1和α(2)δ-2亚基结合，但在多个系统中对钙电流几乎没有急性影响。然而，我们最近的结果确凿地表明，在异源表达系统和背根神经节神经元中，加巴喷丁长期应用时会抑制钙电流，而急性应用时则不会。(1) 在该研究中，我们仅检测了加巴喷丁孵育40小时的时间点，在此我们扩展了这些结果，纳入了加巴喷丁孵育长达6小时和20小时对由Ca(V)2.1/β(4)/α(2)δ-2亚基形成的钙通道电流的影响。如果在记录前加入加巴喷丁17 - 20小时，它能显著有效地抑制电流，但如果加入3 - 6小时则不会产生显著抑制作用。我们之前得出结论，加巴喷丁主要作用于细胞内位点，需要摄取进入细胞。然而，这种作用是由α(2)δ亚基介导的，α(2)δ-1或α(2)δ-2中的突变消除加巴喷丁结合后可阻止这种作用。(1) 此外，我们还表明加巴喷丁会破坏α(2)δ-2和Ca(V)2通道的转运。在此我们也扩展了该研究，以表明如果Ca(V)2.1与含有阻止加巴喷丁结合的点突变（R282A）的α(2)δ-2共表达，慢性加巴喷丁不会降低其细胞表面表达。
