Na+/K+-ATPase coupled to endothelin receptor type B stimulates peripheral nerve regeneration via lactate signaling.
Na+/K+-ATPase coupled to endothelin receptor type B stimulates peripheral nerve regeneration via lactate signaling.
复制标题
Na /K -ATP 酶与 B 型内皮素受体偶联，通过乳酸信号传导刺激周围神经再生。
DOI：
10.1111/ejn.13647
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发表时间：
2017
影响因子：
3.4
通讯作者：
S.
中科院分区：
文献类型：
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作者：
Nguyen H. T.;Katano;T.;Matsumura;S.;Funatsu;N.;Pham;M. V.;Fujisawa;JI. and Ito;S.
我们最近证明了内皮素（ET）在功能上与钠离子偶联，钠离子是一种钠离子浓度敏感的钠离子通道，通过ET受体B型（ETBR）释放乳酸，并参与坐骨神经横断再生小鼠模型的周围神经再生。已知Naxis直接与Na+/K+‐atp酶相互作用，导致脑内乳酸生成。为了研究Na+/K+‐atp酶在周围神经再生中的作用，在这项研究中，我们用渗透泵将Na+/K+‐atp酶抑制剂瓦巴因（ouabain）应用于切口部位4周。而脚趾的功能恢复和神经再生则在截骨后5周开始，7周完成，而瓦巴因将其推迟了2周。乳酸可以改善瓦巴因的延迟，而广泛的单羧酸转运体（MCT）抑制剂α‐氰基‐4‐羟基‐肉桂酸（CIN）可以阻断其作用。在背根神经节原代培养中，乌巴因抑制了神经元的突起生长和乳酸释放到培养基中。相反，乳酸促进神经突生长，这被CIN阻断，但不被AR - C155858 （MCT1/2选择性抑制剂）阻断。ET‐1和ET‐3增加了神经元的神经突生长，而ETBR拮抗剂、瓦巴因和2种蛋白激酶C抑制剂可以减弱这种作用。结合ETBR在雪旺细胞中表达的发现，这些结果表明，ET通过ETBR增强了雪旺细胞中Na+/K+‐atp酶介导的神经元的神经突生长。这项研究表明，Na+/K+‐atp酶偶联到ET‐ETBR系统通过乳酸信号传导在周围神经再生中起关键作用。
We have recently demonstrated that endothelin (ET) is functionally coupled to Nax, a Na+concentration‐sensitive Na+channel for lactate release via ET receptor type B (ETBR) and is involved in peripheral nerve regeneration in a sciatic nerve transection–regeneration mouse model. Naxis known to interact directly with Na+/K+‐ATPase, leading to lactate production in the brain. To investigate the role of Na+/K+‐ATPase in peripheral nerve regeneration, in this study, we applied ouabain, a Na+/K+‐ATPase inhibitor, to the cut site for 4 weeks with an osmotic pump. While functional recovery and nerve reinnervation to the toe started at 5 weeks after axotomy and were completed by 7 weeks, ouabain delayed them by 2 weeks. The delay by ouabain was improved by lactate, and its effect was blocked by α‐cyano‐4‐hydroxy‐cinnamic acid (CIN), a broad monocarboxylate transporter (MCT) inhibitor. In primary cultures of dorsal root ganglia, neurite outgrowth of neurons and lactate release into the culture medium was inhibited by ouabain. Conversely, lactate enhanced the neurite outgrowth, which was blocked by CIN, but not by AR‐C155858, a MCT1/2‐selective inhibitor. ET‐1 and ET‐3 increased neurite outgrowth of neurons, which was attenuated by an ETBR antagonist, ouabain and 2 protein kinase C inhibitors. Taken together with the finding that ETBR was expressed in Schwann cells, these results demonstrate that ET enhanced neurite outgrowth of neurons mediated by Na+/K+‐ATPase via ETBR in Schwann cells. This study suggests that Na+/K+‐ATPase coupled to the ET‐ETBR system plays a critical role in peripheral nerve regeneration via lactate signalling.