Cyclooxygenase-2, prostaglandin E2 glycerol ester and nitric oxide are involved in muscarine-induced presynaptic enhancement at the vertebrate neuromuscular junction.
Cyclooxygenase-2, prostaglandin E2 glycerol ester and nitric oxide are involved in muscarine-induced presynaptic enhancement at the vertebrate neuromuscular junction.
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环加氧酶-2、前列腺素 E2 甘油酯和一氧化氮参与毒蕈碱诱导的脊椎动物神经肌肉接头突触前增强。
DOI：
10.1113/jphysiol.2013.256727
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Su,Zheng
中科院分区：
文献类型：
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作者：
Lindgren,ClarkA;Newman,ZacharyL;Morford,JamieJ;Ryan,StevenB;Battani,KathrynA;Su,Zheng
关键点·神经和肌肉之间的突触，称为神经肌肉接头(NMJ)，当M胆碱受体持续激活时，经历一个双相调制，先减少后增加。·最初的抑制是由肌肉合成并释放的内源性大麻2-花生四烯基甘油(2-AG)引起的；然后，2-AG激活突触前神经上的大麻素受体。·在这里提出的工作中，我们探索了导致延迟增强的机制，发现了环氧合酶-2的作用，并将其定位于NMJ的神经胶质细胞中，称为突触周围雪旺细胞(PSCs)，在那里它将2-AG转化为前列腺素E2的甘油酯。·这些结果揭示了调节神经递质释放的复杂机制，涉及神经，先前的工作已经证明，蜥蜴神经肌肉接头(NMJ)上的M胆碱受体的激活可以诱导诱发的神经递质释放的双相调制：最初的抑制，然后是延迟的增强。这种抑郁是由内源性大麻素2-花生烯基甘油(2-AG)从肌肉中释放并与运动神经末梢上的大麻素1型受体结合所介导的。这项工作表明，神经递质释放的延迟增强是由环氧合酶-2(COX-2)介导的，因为它将2-AG转化为前列腺素E2的甘油酯(PGE2-G)。应用免疫荧光技术，在NMJ周围的突触周围雪旺细胞(PSCs)中检测到COX-2。用选择性COX-2抑制剂尼美舒利或DUP 697预处理，可阻止通常由毒扁豆碱引起的终板电位(EPP)幅度的延迟性增加。PGE2-G可促进神经递质的释放，这与其作为延迟性毒鼠强效应的中介物的假定作用一致。具体地说，PGE2-G增加了EPPS的幅度，而不改变自发的微型EPPS的幅度。如前所述，前列腺素E_2-G对诱发的神经递质释放的增强依赖于一氧化氮(NO)，因为这种反应可被NO合成的抑制剂N-硝基-L-精氨酸甲酯(N-NAME)或NO的螯合剂羧基-PTIO所消除。有趣的是，前列腺素受体拮抗剂AH6809并不能阻止这种增强，但TRPV1和TRPM8受体拮抗剂卡萨西平却能阻断这种增强。综上所述，这些结果表明，COX-2将2-AG转化为PGE2-G是毒鼠碱促进脊椎动物NMJ神经递质释放的基础。
Key points•The synapse between a nerve and muscle, called the neuromuscular junction (NMJ), undergoes a biphasic modulation, a decrease followed by an increase, when muscarinic acetylcholine receptors are continuously activated.•The initial depression is caused by the endocannabinoid 2‐arachidonylglycerol (2‐AG), which is synthesized in and released from the muscle; 2‐AG then activates cannabinoid receptors on the presynaptic nerve.•In the work presented here, we explored the mechanism responsible for the delayed enhancement, uncovering a role for the enzyme cyclooxygenase‐2 and locating it in the glial cells at the NMJ called perisynaptic Schwann cells (PSCs) where it converts 2‐AG into the glycerol ester of prostaglandin E2.•These results reveal a complex mechanism for regulating neurotransmitter release that involves the nerve, muscle and PSCs (i.e. the tripartite synapse) and may serve to ensure reliable neuromuscular transmission during periods of intense or long‐term activity.AbstractPrevious work has demonstrated that activation of muscarinic acetylcholine receptors at the lizard neuromuscular junction (NMJ) induces a biphasic modulation of evoked neurotransmitter release: an initial depression followed by a delayed enhancement. The depression is mediated by the release of the endocannabinoid 2‐arachidonylglycerol (2‐AG) from the muscle and its binding to cannabinoid type 1 receptors on the motor nerve terminal. The work presented here suggests that the delayed enhancement of neurotransmitter release is mediated by cyclooxygenase‐2 (COX‐2) as it converts 2‐AG to the glycerol ester of prostaglandin E2 (PGE2‐G). Using immunofluorescence, COX‐2 was detected in the perisynaptic Schwann cells (PSCs) surrounding the NMJ. Pretreatment with either of the selective COX‐2 inhibitors, nimesulide or DuP 697, prevents the delayed increase in endplate potential (EPP) amplitude normally produced by muscarine. In keeping with its putative role as a mediator of the delayed muscarinic effect, PGE2‐G enhances evoked neurotransmitter release. Specifically, PGE2‐G increases the amplitude of EPPs without altering that of spontaneous miniature EPPs. As shown previously for the muscarinic effect, the enhancement of evoked neurotransmitter release by PGE2‐G depends on nitric oxide (NO) as the response is abolished by application of eitherNG‐nitro‐l‐arginine methyl ester (l‐NAME), an inhibitor of NO synthesis, or carboxy‐PTIO, a chelator of NO. Intriguingly, the enhancement is not prevented by AH6809, a prostaglandin receptor antagonist, but is blocked by capsazepine, a TRPV1 and TRPM8 receptor antagonist. Taken together, these results suggest that the conversion of 2‐AG to PGE2‐G by COX‐2 underlies the muscarine‐induced enhancement of neurotransmitter release at the vertebrate NMJ.