Pain-associated signals, acidosis and lysophosphatidic acid, modulate the neuronal K2P2.1 channel
Pain-associated signals, acidosis and lysophosphatidic acid, modulate the neuronal K2P2.1 channel
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DOI：
10.1016/j.mcn.2008.12.004
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Zilberberg, Noam
中科院分区：
文献类型：
--
作者：
Cohen, Asi;Sagron, Revital;Zilberberg, Noam
疼痛是一种促进对有害事件的保护性反应的生理状态。然而，疼痛可能成为病理生理性的，并成为一种慢性破坏性疾病，损害生活质量。哺乳动物的K（2 P）2.1（KCNK 2，TREK-1）通道，在背根神经节的感觉神经元中表达，以前被确定为参与疼痛感知的多模态分子传感器。在这里，我们报告了两种疼痛相关信号，外部酸中毒和溶血磷脂酸（LPA），已知在损伤，炎症和癌症期间升高，深刻下调人类K（2 P）2.1活性。pH调节作用是通过激活质子敏感的G蛋白偶联受体和磷脂酶C介导的。生理浓度的LPA通过激活刺激G1途径的细胞表面受体而克服已知K（2 P）2.1激活剂如花生四烯酸、溶血磷脂酰胆碱和温度的影响。此外，我们确定了三个K（2 P）2.1羧基末端残基介导的pH值和LPA的调节作用。我们的研究结果强调了K（2 P）2.1通道作为已知引起伤害感受的介质受体的重要作用，（C）2008 Elsevier Inc. All rights reserved.
Pain is a physiological state promoting protective responses to harmful episodes. However, pain can become pathophysiological and become a chronic disruptive condition, damaging quality of life. The mammalian K(2P)2.1 (KCNK2, TREK-1) channel, expressed in sensory neurons of the dorsal root ganglia was previously, identified as a polymodal molecular sensor involved in pain perception. Here, we report that two pain-associated signals, external acidosis and lysophosphatidic acid (LPA), known to rise during injury, inflammation and cancer, profoundly down-modulate human K(2P)2.1 activity. The pH regulatory effect was mediated by activation of proton-sensitive G-protein coupled receptors and phospholipase C. Physiological concentrations of LPA overcame the effects of known K(2P)2.1 activators, such as arachidonic acid, lysophosphatidylcholine and temperature, by activating Cell-surface receptors stimulating the G, pathway. Furthermore, we identified three K(2P)2.1 carboxy-terminal residues that mediate both pH and LPA regulatory effects. Our results highlight the important role of K(2P)2.1 channels as receptors for mediators known to Cause nociception, (C) 2008 Elsevier Inc. All rights reserved.