DEG/ENaC/ASIC channels vary in their sensitivity to anti-hypertensive and non-steroidal anti-inflammatory drugs.
DEG/ENaC/ASIC channels vary in their sensitivity to anti-hypertensive and non-steroidal anti-inflammatory drugs.
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DOI：
10.1085/jgp.202012655
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发表时间：
2021-04-05
期刊：
影响因子：
--
通讯作者：
Goodman MB
中科院分区：
文献类型：
--
作者：
Fechner S;D'Alessandro I;Wang L;Tower C;Tao L;Goodman MB
动物生理学依赖于退行性变离子通道、上皮钠通道和酸敏感离子通道(DEG/ENaC/ASICs)。通过测量三种线虫DEG/ENaC/ASIC对阿米洛利类似物和非类固醇抗炎药的敏感性，Fechner等人。表明各个通道都有不同的药理足迹。退化素通道、上皮性钠通道和酸敏离子通道(DEG/ENaC/ASICs)在神经系统感知机械刺激、调节盐稳态和响应酸化等方面发挥着重要作用。它们有两个跨膜区，由一个大的胞外区隔开，被认为是以同聚体或异构体三聚体的形式组装在一起。根据对选定的家族成员的研究，这些通道被认为形成了对抗高血压药物阿米洛利敏感的非电压门控和钠选择性通道。它们也正在成为非类固醇抗炎药(NSAIDs)的靶点。秀丽隐杆线虫有二十多个编码DEG/ENaC/ASIC亚基的基因，这为研究药物敏感性的变异提供了一个极好的机会。在这里，我们分析了线虫DEG/ENaC/ASIC蛋白的一个子集，以检验这一假设，即单个家庭成员不仅在形成同源通道的能力上存在差异，而且在药物敏感性方面也存在差异。我们选择了一组在机械感觉神经元中共表达的线虫DEG/ENaC/ASIC，并在非洲爪哇卵母细胞中表达了功能增益突变体或d突变体。我们发现，只有DEGT-1d、UNC-8d和MEC-4d形成同源通道，并且与MEC-4d和UNC-8d不同，DEGT-1d通道对阿米洛利及其类似物不敏感。据报道，对于大鼠ASIC1a，非甾体抗炎药抑制DEGT-1d和UNC-8d通道。出乎意料的是，MEC-4d被NSAIDs强烈增强，这种作用因胞外域中假定的NSAID结合位点的突变而减弱。总而言之，这些发现表明，并不是所有的DEG/ENaC/ASIC通道都对阿米洛利敏感，非甾体抗炎药既可以抑制这些通道，也可以增强这些通道。
Animal physiology depends on degenerin, epithelial sodium, and acid-sensing ion channels (DEG/ENaC/ASICs). By measuring the sensitivity of three C. elegans DEG/ENaC/ASICs to amiloride analogs and NSAIDs, Fechner et al. show that individual channels have distinct pharmacological footprints. The degenerin channels, epithelial sodium channels, and acid-sensing ion channels (DEG/ENaC/ASICs) play important roles in sensing mechanical stimuli, regulating salt homeostasis, and responding to acidification in the nervous system. They have two transmembrane domains separated by a large extracellular domain and are believed to assemble as homomeric or heteromeric trimers. Based on studies of selected family members, these channels are assumed to form nonvoltage-gated and sodium-selective channels sensitive to the anti-hypertensive drug amiloride. They are also emerging as a target of nonsteroidal anti-inflammatory drugs (NSAIDs). Caenorhabditis elegans has more than two dozen genes encoding DEG/ENaC/ASIC subunits, providing an excellent opportunity to examine variations in drug sensitivity. Here, we analyze a subset of the C. elegans DEG/ENaC/ASIC proteins to test the hypothesis that individual family members vary not only in their ability to form homomeric channels but also in their drug sensitivity. We selected a panel of C. elegans DEG/ENaC/ASICs that are coexpressed in mechanosensory neurons and expressed gain-of-function or d mutants in Xenopus laevis oocytes. We found that only DEGT‑1d, UNC‑8d, and MEC‑4d formed homomeric channels and that, unlike MEC‑4d and UNC‑8d, DEGT‑1d channels were insensitive to amiloride and its analogues. As reported for rat ASIC1a, NSAIDs inhibit DEGT‑1d and UNC‑8d channels. Unexpectedly, MEC‑4d was strongly potentiated by NSAIDs, an effect that was decreased by mutations in the putative NSAID-binding site in the extracellular domain. Collectively, these findings reveal that not all DEG/ENaC/ASIC channels are amiloride-sensitive and that NSAIDs can both inhibit and potentiate these channels.
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影响因子：
4.8
作者：
Elkhatib, Wassim;Smith, Carolyn L.;Senatore, Adriano
通讯作者：
Senatore, Adriano
影响因子：
4.8
作者：
Adams, CM;Snyder, PM;Welsh, MJ
通讯作者：
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影响因子：
64.8
作者：
Gonzales, Eric B.;Kawate, Toshimitsu;Gouaux, Eric
通讯作者：
Gouaux, Eric
DOI：
10.1152/physiol.00006.2012
发表时间：
2012-10
期刊：
Physiology (Bethesda, Md.)
影响因子：
--
作者：
Eastwood AL;Goodman MB
通讯作者：
Goodman MB
DOI：
10.1895/wormbook.1.161.1
发表时间：
2013-08-13
期刊：
WormBook : the online review of C. elegans biology
影响因子：
--
作者：
Hobert, Oliver
通讯作者：
Hobert, Oliver