An EP2 Agonist Facilitates NMDA-Induced Outward Currents and Inhibits Dendritic Beading through Activation of BK Channels in Mouse Cortical Neurons.
An EP2 Agonist Facilitates NMDA-Induced Outward Currents and Inhibits Dendritic Beading through Activation of BK Channels in Mouse Cortical Neurons.
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DOI：
10.1155/2016/5079597
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发表时间：
2016
影响因子：
4.6
通讯作者：
Nakanishi H
中科院分区：
文献类型：
--
作者：
Hayashi Y;Morinaga S;Liu X;Zhang J;Wu Z;Yokoyama T;Nakanishi H
前列腺素E2(PGE2)是环氧合酶途径产生的花生四烯酸的主要代谢物，通过激活EP1、EP2、EP3和EP4四种E-前列腺素受体亚型发挥其生物活性作用。PGE2可以调节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)通道的影响尚不清楚。在这里，我们发现EP2受体介导的信号通路增加了NMDA诱导的外向电流(I NMDA-OUT)，这与BK通道的激活有关。急性分离的小鼠皮质神经元的膜片钳记录显示，EP2受体激动剂激活了I-NMDA-OUT，而EP3受体激动剂则降低了它。EP1或EP4受体激动剂对I-NMDA-OUT无明显影响。通过膜片管直接灌流3，5‘-环磷酸腺苷(CAMP)可促进I-NMDA-Out，这种作用可被蛋白激酶A(PKA)抑制剂所阻断。此外，由EP2受体激动剂引起的I-NMDA-out的易化可被PKA抑制剂显著抑制。最后，通过EP2受体激活BK通道促进了NMDA诱导的原代培养皮层神经元树突珠形成的恢复期。这些结果表明，EP2受体介导的信号通路直接激活BK通道对大脑皮层神经元具有神经保护作用。
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 Ca2+-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.