NSAIDs Naproxen, Ibuprofen, Salicylate, and Aspirin Inhibit TRPM7 Channels by Cytosolic Acidification.
NSAIDs Naproxen, Ibuprofen, Salicylate, and Aspirin Inhibit TRPM7 Channels by Cytosolic Acidification.
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DOI：
10.3389/fphys.2021.727549
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发表时间：
2021
影响因子：
4
通讯作者：
Kozak JA
中科院分区：
文献类型：
--
作者：
Chokshi R;Bennett O;Zhelay T;Kozak JA
非甾体抗炎药（NSAID）用于缓解伴随许多疾病状态的疼痛和炎症。这些广泛使用的药物的主要治疗机制是抑制环氧合酶1和2（COX 1，2）酶，所述酶催化花生四烯酸转化为胡萝卜素。在较高剂量下，NSAID用于预防某些类型的癌症和作为阿尔茨海默病的实验性治疗。在免疫系统中，已报道各种NSAID影响中性粒细胞功能和淋巴细胞增殖，并影响离子通道和细胞钙稳态。瞬时受体电位melastatin 7（TRPM 7）阳离子通道在T淋巴细胞中高度表达，并被Mg 2+、酸性pH和多胺抑制。在这里，我们报告了萘普生，布洛芬，水杨酸盐和乙酰水杨酸盐对TRPM 7的新作用。在3- 30 mM的浓度下，它们可逆地抑制TRPM 7通道电流。通过用比率指示剂BCECF测量细胞内pH，我们发现在300μM至30 mM时，这些NSAID以浓度依赖性方式可逆地酸化细胞质，并提出TRPM 7通道抑制是胞质酸化的结果，而不是直接的。NSAID对TRPM 7通道的抑制是缓慢的、电压非依赖性的，并且显示出使用依赖性，在重复药物应用后效力增加。水杨酸盐的通道抑制程度强烈依赖于细胞PI（4，5）P2水平，当这种磷脂被耗尽电压敏感性脂质磷酸酶（VSP）。水杨酸盐抑制异源表达的野生型TRPM 7通道，但不抑制S1107 R变体，其对胞质pH、Mg 2+和PI（4，5）P2消耗不敏感。在果蝇（一种缺乏正向考克斯基因的生物体）的Schneider 2细胞中也观察到NSAID诱导的酸化，表明该效应与考克斯酶活性无关。暴露于300μM-10 mM萘普生24小时导致细胞活力浓度依赖性降低。除了TRPM 7之外，预期所描述的NSAID作用适用于对细胞内pH敏感的其他离子通道和转运蛋白。
Non-steroidal anti-inflammatory drugs (NSAIDs) are used for relieving pain and inflammation accompanying numerous disease states. The primary therapeutic mechanism of these widely used drugs is the inhibition of cyclooxygenase 1 and 2 (COX1, 2) enzymes that catalyze the conversion of arachidonic acid into prostaglandins. At higher doses, NSAIDs are used for prevention of certain types of cancer and as experimental treatments for Alzheimer’s disease. In the immune system, various NSAIDs have been reported to influence neutrophil function and lymphocyte proliferation, and affect ion channels and cellular calcium homeostasis. Transient receptor potential melastatin 7 (TRPM7) cation channels are highly expressed in T lymphocytes and are inhibited by Mg2+, acidic pH, and polyamines. Here, we report a novel effect of naproxen, ibuprofen, salicylate, and acetylsalicylate on TRPM7. At concentrations of 3–30mM, they reversibly inhibited TRPM7 channel currents. By measuring intracellular pH with the ratiometric indicator BCECF, we found that at 300μM to 30mM, these NSAIDs reversibly acidified the cytoplasm in a concentration-dependent manner, and propose that TRPM7 channel inhibition is a consequence of cytosolic acidification, rather than direct. NSAID inhibition of TRPM7 channels was slow, voltage-independent, and displayed use-dependence, increasing in potency upon repeated drug applications. The extent of channel inhibition by salicylate strongly depended on cellular PI(4,5)P2 levels, as revealed when this phospholipid was depleted with voltage-sensitive lipid phosphatase (VSP). Salicylate inhibited heterologously expressed wildtype TRPM7 channels but not the S1107R variant, which is insensitive to cytosolic pH, Mg2+, and PI(4,5)P2 depletion. NSAID-induced acidification was also observed in Schneider 2 cells from Drosophila, an organism that lacks orthologous COX genes, suggesting that this effect is unrelated to COX enzyme activity. A 24-h exposure to 300μM–10mM naproxen resulted in a concentration-dependent reduction in cell viability. In addition to TRPM7, the described NSAID effect would be expected to apply to other ion channels and transporters sensitive to intracellular pH.
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DOI：
10.1111/febs.15683
发表时间：
2021-06
期刊：
The FEBS journal
影响因子：
--
作者：
Beesetty P;Rockwood J;Kaitsuka T;Zhelay T;Hourani S;Matsushita M;Kozak JA
通讯作者：
Kozak JA
影响因子：
7.3
作者：
Freichel M;Almering J;Tsvilovskyy V
通讯作者：
Tsvilovskyy V
DOI：
10.1073/pnas.89.21.10375
发表时间：
1992-11-01
影响因子：
11.1
作者：
ABRAMS, JM;LUX, A;KRIEGER, M
通讯作者：
KRIEGER, M
影响因子：
4.8
作者：
Frolov, Roman V.;Berim, Ilya G.;Singh, Satpal
通讯作者：
Singh, Satpal
影响因子：
3.5
作者：
Deason-Towne, Francina;Perraud, Anne-Laure;Schmitz, Carsten
通讯作者：
Schmitz, Carsten