Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.
Toxicol Lett. 2013 Nov 25;223(2):139-45. doi: 10.1016/j.toxlet.2013.08.021. Epub 2013 Sep 4.
Methamphetamine (MA), a highly abused amphetamine-like psychostimulant, has surged in popularity worldwide in the last decade. Repeated MA exposure has been shown to affect the alternative splice variant expression of large conductance Ca(2+)-activated K(+) (BK) channels. It remains unclear whether MA affects BK channel activity. The present study investigated the effects of MA on BK channels in NG108-15 mouse neuroblastoma×rat glioma hybrid cells using whole-cell and cell-attached patch clamp techniques. In whole-cell recordings, the macroscopic K(+) outward currents were inhibited by MA with an EC50 of 146μM, but not affected by dopamine (DA). It implies that DA is not involved in the effects of MA on K(+) outward currents. In cell-attached patches, MA significantly decreased BK channel activity. Moreover, MA significantly decreased the BK channel opener NS1619-evoked whole-cell K(+) outward currents and BK channel activity. Finally, the effect of MA on membrane potential was examined by current-clamp configuration. MA caused membrane depolarization and application of NS1619 returned the depolarized potential to resting value. These findings suggest that MA might act as an inhibitor of BK channels, and thereby increase the neuronal excitability and enhance neurotransmitter release.
甲基苯丙胺（MA）是一种高度滥用的苯丙胺类精神兴奋剂，在过去十年中在全球范围内流行起来。反复暴露于 MA 已被证明会影响大电导钙激活钾（BK）通道的替代剪接变体表达。目前尚不清楚 MA 是否会影响 BK 通道活性。本研究使用全细胞和细胞贴附式膜片钳技术研究 MA 对 NG108-15 小鼠神经母细胞瘤×大鼠神经胶质瘤杂交细胞中 BK 通道的影响。在全细胞记录中，MA 以 EC50 为 146μM 抑制了宏观 K+外向电流，但不受多巴胺（DA）影响。这表明 DA 不参与 MA 对 K+外向电流的影响。在细胞贴附式膜片中，MA 显著降低了 BK 通道活性。此外，MA 显著降低了 BK 通道 opener NS1619 诱发的全细胞 K+外向电流和 BK 通道活性。最后，通过电流钳配置检查 MA 对膜电位的影响。MA 引起膜去极化，而 NS1619 的应用将去极化电位恢复到静息值。这些发现表明 MA 可能作为 BK 通道的抑制剂，从而增加神经元兴奋性并增强神经递质释放。
