Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling
Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling
复制标题
DOI：
10.1016/j.neuron.2017.02.025
复制
发表时间：
2017-03-22
期刊：
影响因子：
16.2
通讯作者：
Bean, Bruce P.
中科院分区：
文献类型：
--
作者：
Gantz, Stephanie C.;Bean, Bruce P.
哺乳动物大脑中主要的内源性大麻素是生物活性脂质 2-花生四烯酰甘油 (2-AG)。 2-AG 最著名的作用是由 G 蛋白偶联大麻素受体介导的。原则上，2-AG 可以通过直接作用于离子通道来改变神经元的兴奋性，但人们对这种机制知之甚少。使用分离的小鼠中脑多巴胺神经元的制剂来分离对内在兴奋性的影响，我们发现 100 nM 2-AG 加速了起搏并使爆发式放电的频率-电流关系变得陡峭。在电压钳实验中，2-AG 通过模仿花生四烯酸的大麻素受体独立机制降低 A 型钾电流 (IA)，而花生四烯酸对大麻素受体没有活性。食欲素、神经降压素和代谢型谷氨酸 G(q/11) 连接受体的激活模拟了外源 2-AG 的作用，并且通过抑制 2-AG 合成酶二酰甘油脂肪酶 α 来阻止它们的作用。结果表明，2-AG和相关脂质信号分子可以通过调节I-A以细胞自主的方式直接调节神经元兴奋性。
The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate G(q/11)-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase alpha. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating I-A.