Hayashi Yoshinori, Morinaga Saori, Liu Xia, Zhang Jing, Wu Zhou, Yokoyama Takeshi, Nakanishi Hiroshi
Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Dental Anesthesiology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Mediators Inflamm. 2016;2016:5079597. doi: 10.1155/2016/5079597. Epub 2016 May 19.
Prostaglandin E2 (PGE2), a major metabolite of arachidonic acid produced by cyclooxygenase pathways, exerts its bioactive responses by activating four E-prostanoid receptor subtypes, EP1, EP2, EP3, and EP4. PGE2 enables modulating N-methyl-D-aspartate (NMDA) receptor-mediated responses. However, the effect of E-prostanoid receptor agonists on large-conductance Ca(2+)-activated K(+) (BK) channels, which are functionally coupled with NMDA receptors, remains unclear. Here, we showed that EP2 receptor-mediated signaling pathways increased NMDA-induced outward currents (I NMDA-OUT), which are associated with the BK channel activation. Patch-clamp recordings from the acutely dissociated mouse cortical neurons revealed that an EP2 receptor agonist activated I NMDA-OUT, whereas an EP3 receptor agonist reduced it. Agonists of EP1 or EP4 receptors showed no significant effects on I NMDA-OUT. A direct perfusion of 3,5'-cyclic adenosine monophosphate (cAMP) through the patch pipette facilitated I NMDA-OUT, which was abolished by the presence of protein kinase A (PKA) inhibitor. Furthermore, facilitation of I NMDA-OUT caused by an EP2 receptor agonist was significantly suppressed by PKA inhibitor. Finally, the activation of BK channels through EP2 receptors facilitated the recovery phase of NMDA-induced dendritic beading in the primary cultured cortical neurons. These results suggest that a direct activation of BK channels by EP2 receptor-mediated signaling pathways plays neuroprotective roles in cortical neurons.
前列腺素E2（PGE2）是由环氧化酶途径产生的花生四烯酸的主要代谢产物，它通过激活四种E-前列腺素受体亚型EP1、EP2、EP3和EP4发挥其生物活性反应。PGE2能够调节N-甲基-D-天冬氨酸（NMDA）受体介导的反应。然而，E-前列腺素受体激动剂对与NMDA受体功能偶联的大电导钙激活钾（BK）通道的影响仍不清楚。在此，我们表明EP2受体介导的信号通路增加了与BK通道激活相关的NMDA诱导的外向电流（I NMDA-OUT）。对急性解离的小鼠皮层神经元进行的膜片钳记录显示，EP2受体激动剂激活了I NMDA-OUT，而EP3受体激动剂则降低了该电流。EP1或EP4受体激动剂对I NMDA-OUT没有显著影响。通过膜片吸管直接灌注3,5'-环磷酸腺苷（cAMP）促进了I NMDA-OUT，而蛋白激酶A（PKA）抑制剂的存在则消除了这种促进作用。此外，PKA抑制剂显著抑制了EP2受体激动剂引起的I NMDA-OUT促进作用。最后，通过EP2受体激活BK通道促进了原代培养皮层神经元中NMDA诱导的树突珠化的恢复阶段。这些结果表明，EP2受体介导的信号通路直接激活BK通道在皮层神经元中发挥神经保护作用。
