Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Department of Ophthalmology at Eye & ENT Hospital, Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China.
Neuropharmacology. 2017 Sep 15;124:143-156. doi: 10.1016/j.neuropharm.2017.04.027. Epub 2017 Apr 18.
Endocannabinoid signaling system is involved in regulating multiple neuronal functions in the central nervous system by activating G-protein coupled cannabinoid CB1 and CB2 receptors (CB1Rs and CB2Rs). Growing evidence has shown that CB1Rs and CB2Rs are extensively expressed in retinal ganglion cells (RGCs). Here, modulation of L- and T-types Ca channels by activating CB1Rs and CB2Rs in RGCs was investigated. Triple immunofluorescent staining showed that L-type subunit Ca1.2 was co-localized with T-type subunits (Ca3.1, Ca3.2 and Ca3.3) in rat RGCs. In acutely isolated rat RGCs, the CB1R agonist WIN55212-2 suppressed both peak and steady-state Ca currents in a dose-dependent manner, with IC being 9.6 μM and 8.4 μM, respectively. It was further shown that activation of CB1Rs by WIN55212-2 or ACEA, another CB1R agonist, significantly suppressed both L- and T-type Ca currents, and shifted inactivation curve of T-type one toward hyperpolarization direction. While the effect on L-type Ca channels was mediated by intracellular cAMP/protein kinase A (PKA), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and calcium/calmodulin-dependent protein kinase II (CaMKII) signaling pathways, only CaMKII signaling pathway was involved in the effect on T-type Ca channels. Furthermore, CB65 and HU308, two specific CB2R agonists, significantly suppressed T-type Ca channels, which was mediated by intracellular cAMP/PKA and CaMKII signaling pathways, but had no effect on L-type channels. These results imply that endogenous cannabinoids may modulate the excitability and the output of RGCs by differentially suppressing the activity of L- and T-type Ca channels through activation of CB1Rs and CB2Rs. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".
内源性大麻素信号系统通过激活 G 蛋白偶联大麻素 CB1 和 CB2 受体 (CB1R 和 CB2R) 来调节中枢神经系统中的多种神经元功能。越来越多的证据表明，CB1R 和 CB2R 在视网膜神经节细胞 (RGCs) 中广泛表达。在这里，研究了激活 RGCs 中的 CB1R 和 CB2R 对 L 和 T 型钙通道的调制。三重免疫荧光染色显示，L 型亚基 Ca1.2 与 T 型亚基 (Ca3.1、Ca3.2 和 Ca3.3) 在大鼠 RGCs 中共定位。在急性分离的大鼠 RGCs 中，CB1R 激动剂 WIN55212-2 以剂量依赖性方式抑制峰和稳态 Ca 电流，IC 分别为 9.6 μM 和 8.4 μM。进一步表明，WIN55212-2 或另一种 CB1R 激动剂 ACEA 激活 CB1R 可显著抑制 L 和 T 型 Ca 电流，并使 T 型失活曲线向超极化方向移动。虽然对 L 型 Ca 通道的作用是通过细胞内 cAMP/蛋白激酶 A (PKA)、丝裂原激活蛋白激酶 (MAPK)/细胞外信号调节激酶 (ERK) 和钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) 信号通路介导的，但只有 CaMKII 信号通路参与了对 T 型 Ca 通道的作用。此外，两种特定的 CB2R 激动剂 CB65 和 HU308 显著抑制 T 型 Ca 通道，该作用是通过细胞内 cAMP/PKA 和 CaMKII 信号通路介导的，但对 L 型通道没有影响。这些结果表明，内源性大麻素可能通过激活 CB1R 和 CB2R 来抑制 L 和 T 型 Ca 通道的活性，从而调节 RGCs 的兴奋性和输出。本文是题为“大麻素神经生物学的新纪元”的特刊的一部分。
