Karanian David A, Brown Queenie B, Makriyannis Alexandros, Bahr Ben A
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-2092, USA.
Eur J Pharmacol. 2005 Jan 31;508(1-3):47-56. doi: 10.1016/j.ejphar.2004.12.009. Epub 2005 Jan 7.
The cannabinoid CB1 receptor allows endocannabinoids to act as intercellular and retrograde messengers in the central nervous system. Endocannabinoid actions have been implicated in both synaptic plasticity and neuroprotection. Here, cannabinergic activation of extracellular signal regulated-kinase (ERK) and focal adhesion kinase (FAK) occurred correspondingly in long-term hippocampal slice cultures. The stable endocannabinoid analogue R-methanandamide activated ERK1/ERK2 subtypes of mitogen-activated protein kinase (MAPK) through the upstream activator MAPK kinase (MEK). R-methanandamide also promoted FAK signaling, but in a MEK-independent manner. Both events of ERK and FAK activation were selectively blocked by N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281), a cannabinoid CB1 receptor antagonist, and the blockage was associated with a gradual decline in synaptic markers. Interestingly, the integrin antagonist Gly-Arg-Gly-Asp-Ser-Pro also caused the disruption of R-methanandamide-mediated ERK and FAK responses and upset the integrity of excitatory synapses. These results suggest that the endocannabinoid system supports synaptic maintenance through linkages with MAPK pathways and integrin-related FAK signaling.
大麻素CB1受体可使内源性大麻素在中枢神经系统中充当细胞间和逆行信使。内源性大麻素的作用与突触可塑性和神经保护均有关联。在此，在长期海马脑片培养物中相应地出现了细胞外信号调节激酶（ERK）和粘着斑激酶（FAK）的大麻素能激活。稳定的内源性大麻素类似物R-甲烷基大麻酰胺通过上游激活剂丝裂原活化蛋白激酶激酶（MEK）激活有丝分裂原活化蛋白激酶（MAPK）的ERK1/ERK2亚型。R-甲烷基大麻酰胺还以MEK非依赖的方式促进FAK信号传导。ERK和FAK激活这两个事件均被大麻素CB1受体拮抗剂N-（吗啉-4-基）-1-（2,4-二氯苯基）-5-（4-碘苯基）-4-甲基-1H-吡唑-3-甲酰胺（AM281）选择性阻断，且这种阻断与突触标志物的逐渐减少有关。有趣的是，整合素拮抗剂甘氨酸-精氨酸-甘氨酸-天冬氨酸-丝氨酸-脯氨酸也导致R-甲烷基大麻酰胺介导的ERK和FAK反应中断，并破坏了兴奋性突触的完整性。这些结果表明，内源性大麻素系统通过与MAPK途径和整合素相关的FAK信号传导的联系来支持突触维持。
