Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons.
Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons.
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DOI：
10.1152/jn.1997.78.1.43
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发表时间：
1997-07
影响因子：
2.5
通讯作者：
W. Twitchell;Sean P. Brown;K. Mackie
中科院分区：
文献类型：
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作者：
W. Twitchell;Sean P. Brown;K. Mackie
已发现大麻素及其类似物抑制用大麻素CB 1受体转染的细胞系和交感神经元中的N-和P/Q-型Ca 2+电流。然而，大麻素对CNS中Ca 2+电流的影响在很大程度上尚未探索。在这项研究中，我们研究了这些化合物是否抑制培养的大鼠海马神经元中的Ca 2+通道。使用针对CB 1受体的氨基末端的抗体，我们发现，在5天的培养物中，圆形的神经元表达体细胞CB 1受体，而在4周的培养物中，受体主要位于神经突上。在早期培养物中，大麻模拟物WIN 55，212 -2以浓度依赖性（K（1/2）= 21 nM）和百日咳毒素敏感性方式可逆地抑制全细胞Ba 2+电流。CB 1拮抗剂SR 141716可降低抑制作用。电流不受非精神活性对映体WIN 55，212 -3的影响。非经典大麻素激动剂CP 55，940和内源性大麻素anandamide的最大抑制作用与最大浓度的WIN 55，212 -2相似。大麻素调节的Ba ~（2+）电流由N型（ω-芋螺毒素-GVIA-敏感）和P/Q型（ω-芋螺毒素-MVIIC-敏感）通道传递。这些结果表明大麻素受体介导的抑制中枢神经元中不同的Ca 2+通道。由于这些电流的基础通道主要位于突触前，并需要诱发神经递质的释放，我们的研究结果表明大麻素（内源性和外源性）在中枢神经系统突触的突触传递的调制中的重要作用。
Cannabinoids and their analogues have been found to inhibit N- and P/Q-type Ca2+ currents in cell lines and sympathetic neurons transfected with cannabinoid CB1 receptor. However, the effects of cannabinoids on Ca2+ currents in the CNS are largely unexplored. In this study we investigated whether these compounds inhibit Ca2+ channels in cultured rat hippocampal neurons. With the use of antibodies directed against the amino-terminus of the CB1 receptor, we found that in 5-day cultures pyramidally shaped neurons expressed somatic CB1 receptors, whereas in 4-wk cultures the receptor was predominately located on neurites. In early cultures, the cannabimimetic WIN 55,212-2 reversibly inhibited whole cell Ba2+ current in a concentration-dependent (K(1/2) = 21 nM) and pertussis-toxin-sensitive fashion. Inhibition was reduced by the CB1 antagonist SR141716. The current was unaffected by the nonpsychoactive enantiomer WIN 55,212-3. Maximal inhibition by the nonclassical cannabinoid agonist CP 55,940 and by an endogenous cannabinoid, anandamide, were similar to that seen with maximal concentrations of WIN 55,212-2. The Ba2+ current modulated by cannabinoids was carried by N-type (omega-conotoxin-GVIA-sensitive) and P/Q-type (omega-conotoxin-MVIIC-sensitive) channels. These results demonstrate cannabinoid-receptor-mediated inhibition of distinct Ca2+ channels in central neurons. Because the channels that underlie these currents are chiefly located presynaptically, and are required for evoked neurotransmitter release, our results suggest a major role for cannabinoids (endogenous and exogenous) in the modulation of synaptic transmission at CNS synapses.