Extracellular histone proteins activate P2XR7 channel current.
Extracellular histone proteins activate P2XR7 channel current.
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DOI：
10.1085/jgp.202213317
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发表时间：
2023-07-03
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--
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众所周知，组蛋白在循环中升高，从而导致血管功能障碍。然而，有关作用机制的许多细节尚不清楚。在这里，作者证明了在异源表达系统中，细胞外应用组蛋白激活了P2XR7通道电流。细胞外组蛋白在损伤或激活先天免疫反应后在循环中升高。在阻力大小的动脉中，细胞外组蛋白增加了内皮细胞(EC)钙内流和碘化丙啶(PI)标记，但却相反地降低了血管扩张。这些观察结果可以通过激活EC驻留的非选择性阳离子通道来解释。我们验证了一种假设，即与阳离子染料摄取相关的非选择性阳离子通道--亲离子嘌呤能受体7(P2XR7)被组蛋白激活。我们在异种细胞中表达了小鼠P2XR7(C57BL/6J变异体451L)，并用双电极电压钳(TEVC)测量了其内向阳离子电流。表达小鼠P2XR7的细胞具有强大的ATP和组蛋白诱发的内向阳离子电流。ATP和组蛋白诱发的电流在大致相同的电位下颠倒。组蛋白诱发的电流随激动剂去除而衰减的速度慢于ATP或BzATP诱发的电流。与ATP诱发的P2XR7电流一样，组蛋白诱发电流可被非选择性的P2XR7拮抗剂(苏拉明、PPADS和TNP-ATP)抑制。选择性的P2XR7拮抗剂AZ10606120、A438079、GW791343和AZ11645373可抑制ATP诱发的P2XR7电流，但不抑制组蛋白诱发的P2XR7电流。与先前关于ATP诱发电流的报道一样，组蛋白诱发的P2XR7电流在细胞外低钙条件下也会增加。这些数据表明，在异源表达系统中，P2XR7对于组蛋白引起的内向阳离子电流是必要的和充分的。这些结果为组蛋白激活P2XR7提供了一种新的变构机制。
Histone proteins are known to be elevated in circulation where they contribute to vascular dysfunction. However, many details regarding the mechanism of action are unknown. Here, the authors show that P2XR7 channel current is activated by extracellularly applied histone proteins in a heterologous expression system. Extracellular histone proteins are elevated in circulation after injury or activation of the innate immune response. In resistance-size arteries, extracellular histone proteins increased endothelial cell (EC) Ca2+ influx and propidium iodide (PI) labeling, but paradoxically decreased vasodilation. These observations could be explained by the activation of an EC resident non-selective cation channel. We tested the hypothesis that the ionotropic purinergic receptor 7 (P2XR7), a non-selective cation channel associated with cationic dye uptake, is activated by histone proteins. We expressed mouse P2XR7 (C57BL/6J variant 451L) in heterologous cells and measured inward cation current using two-electrode voltage clamp (TEVC). Cells expressing mouse P2XR7 had robust ATP- and histone-evoked inward cation currents. ATP- and histone-evoked currents reversed approximately at the same potential. Current decay with agonist removal was slower for histone-evoked than ATP- or BzATP-evoked currents. As with ATP-evoked P2XR7 currents, histone-evoked currents were inhibited by non-selective P2XR7 antagonists (Suramin, PPADS, and TNP-ATP). Selective P2XR7 antagonists, AZ10606120, A438079, GW791343, and AZ11645373, inhibited ATP-evoked P2XR7 currents but did not inhibit histone-evoked P2XR7 currents. As previously reported with ATP-evoked currents, histone-evoked P2XR7 currents were also increased in conditions of low extracellular Ca2+. These data demonstrate that P2XR7 is necessary and sufficient for histone-evoked inward cation currents in a heterologous expression system. These results provide insight into a new allosteric mechanism of P2XR7 activation by histone proteins.
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DOI：
10.1085/jgp.201110647
发表时间：
2011-10
期刊：
The Journal of general physiology
影响因子：
--
作者：
Yan Z;Khadra A;Sherman A;Stojilkovic SS
通讯作者：
Stojilkovic SS
细胞外组蛋白是败血症死亡的主要介体。
影响因子：
82.9
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--
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9
作者：
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影响因子：
64.8
作者：
Gonzales, Eric B.;Kawate, Toshimitsu;Gouaux, Eric
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Gouaux, Eric
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5.8
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