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Phosphocholine – an agonist of metabotropic but not of ionotropic functions of alpha9-containing nicotinic acetylcholine receptors

机译:磷酸胆碱–促代谢的激动剂,而不是含阿尔法9的烟碱乙酰胆碱受体的离子功能的激动剂

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摘要

We demonstrated previously that phosphocholine and phosphocholine-modified macromolecules efficiently inhibit ATP-dependent release of interleukin-1beta from human and murine monocytes by a mechanism involving nicotinic acetylcholine receptors (nAChR). Interleukin-1beta is a potent pro-inflammatory cytokine of innate immunity that plays pivotal roles in host defence. Control of interleukin-1beta release is vital as excessively high systemic levels cause life threatening inflammatory diseases. In spite of its structural similarity to acetylcholine, there are no other reports on interactions of phosphocholine with nAChR. In this study, we demonstrate that phosphocholine inhibits ion-channel function of ATP receptor P2X7 in monocytic cells via nAChR containing alpha9 and alpha10 subunits. In stark contrast to choline, phosphocholine does not evoke ion current responses in Xenopus laevis oocytes, which heterologously express functional homomeric nAChR composed of alpha9 subunits or heteromeric receptors containing alpha9 and alpha10 subunits. Preincubation of these oocytes with phosphocholine, however, attenuated choline-induced ion current changes, suggesting that phosphocholine may act as a silent agonist. We conclude that phophocholine activates immuno-modulatory nAChR expressed by monocytes but does not stimulate canonical ionotropic receptor functions.
机译:我们先前证明,磷酸胆碱和磷酸胆碱修饰的大分子可通过涉及烟碱乙酰胆碱受体(nAChR)的机制有效抑制人和鼠单核细胞的ATP依赖性白细胞介素1β释放。白细胞介素-1β是先天免疫的有效促炎细胞因子,在宿主防御中起关键作用。控制白细胞介素-1β的释放至关重要,因为全身水平过高会导致威胁生命的炎症性疾病。尽管其结构与乙酰胆碱相似,但尚无其他有关磷酸胆碱与nAChR相互作用的报道。在这项研究中,我们证明了磷酸胆碱通过包含alpha9和alpha10亚基的nAChR抑制单核细胞中ATP受体P2X7的离子通道功能。与胆碱形成鲜明对比的是,磷胆碱不会在非洲爪蟾卵母细胞中引起离子电流响应,该卵母细胞异源表达由alpha9亚基或包含alpha9和alpha10亚基的异聚受体组成的功能同源nAChR。然而,将这些卵母细胞与磷胆碱预孵育会减弱胆碱诱导的离子电流变化,表明磷胆碱可能充当沉默的激动剂。我们得出结论,phophocholine激活单核细胞表达的免疫调节nAChR,但不刺激规范的离子受体功能。

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