CANNABINOIDS INHIBIT N-TYPE CALCIUM CHANNELS IN NEUROBLASTOMA GLIOMA-CELLS
CANNABINOIDS INHIBIT N-TYPE CALCIUM CHANNELS IN NEUROBLASTOMA GLIOMA-CELLS
复制标题
DOI：
10.1073/pnas.89.9.3825
复制
发表时间：
1992-05-01
影响因子：
11.1
通讯作者：
HILLE, B
中科院分区：
文献类型：
--
作者：
MACKIE, K;HILLE, B
大麻及其主要生物活性成分DELTA-9-tetrahydrocannabinol的精神活性多年来一直为人所知。最近对一种特定大麻素受体的鉴定和克隆表明，大麻素模仿影响情绪、记忆、运动和疼痛的神经信号的内源性化合物。使用全细胞电压钳和大麻素模拟物氨基烷基吲哚WIN 55，212 -2，我们发现大麻素受体激活降低了神经母细胞瘤-神经胶质瘤细胞系NG 108 -15中电压门控钙电流的幅度。抑制作用是有效的，在小于10 nM时达到半数最大值，并且是可逆的。无活性的对映异构体，WIN 55，212 -3，即使在1 μ M时也不降低钙电流。在NG 108 -15细胞中的几种类型的钙电流中，大麻素主要抑制ω-芋螺毒素敏感的高电压激活的钙电流。与百日咳毒素一起孵育可以阻断抑制作用，但预先用抗水解的cAMP类似物和磷酸二酯酶抑制剂一起处理并没有改变抑制作用，这表明大麻素受体和钙通道之间的转导途径涉及百日咳毒素敏感的GT结合蛋白，并且独立于cAMP代谢。然而，抑制的发展比这些细胞中的α-2-肾上腺素能受体所使用的类似途径慢得多。我们的研究结果表明，抑制N型钙通道，这可能会降低兴奋性和神经递质的释放，可能是大麻素的一些精神活性作用的基础。
The psychoactive properties of Cannabis sativa and its major biologically active constituent, DELTA-9-tetrahydrocannabinol, have been known for years. The recent identification and cloning of a specific cannabinoid receptor suggest that cannabinoids mimic endogenous compounds affecting neural signals for mood, memory, movement, and pain. Using whole-cell voltage clamp and the cannabinomimetic aminoalkylindole WIN 55,212-2, we have found that cannabinoid receptor activation reduces the amplitude of voltage-gated calcium currents in the neuroblastoma-glioma cell line NG108-15. The inhibition is potent, being half-maximal at less than 10 nM, and reversible. The inactive enantiomer, WIN 55,212-3, does not reduce calcium currents even at 1-mu-M. Of the several types of calcium currents in NG108-15 cells, cannabinoids predominantly inhibit an omega-conotoxin-sensitive, high-voltage-activated calcium current. Inhibition was blocked by incubation with pertussis toxin but was not altered by prior treatment with hydrolysis-resistant cAMP analogues together with a phosphodiesterase inhibitor, suggesting that the transduction pathway between the cannabinoid receptor and calcium channel involves a pertussis toxin-sensitive GTP-binding protein and is independent of cAMP metabolism. However, the development of inhibition is considerably slower than a pharmacologically similar pathway used by an alpha-2-adrenergic receptor in these cells. Our results suggest that inhibition of N-type calcium channels, which could decrease excitability and neurotransmitter release, may underlie some of the psychoactive effects of cannabinoids.