Correia Leonor, Shalygin Alexey, Erbacher Anna, Zaisserer Joanna, Gudermann Thomas, Chubanov Vladimir
Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany.
Comprehensive Pneumology Center, German Center for Lung Research (DZL), Munich, Germany.
Arch Toxicol. 2025 May 15. doi: 10.1007/s00204-025-04058-4.
TRPM7 is a kinase-coupled ion channel that exhibits high activity in the immune and epithelial cells of different organs, including the lung. Electrophysiological studies have established that the TRPM7 channel displays high permeability to Mg, Zn, and Ca, as well as trace metal cations. While the critical role of TRPM7 in the cellular balance of Mg, Zn, and Ca is well-documented, its contribution to the cellular uptake of trace metal cations, frequent respiratory pollutants, remains unclear. Here, we performed an electrophysiological assessment of pulmonary A549 cells revealing endogenous TRPM7 currents, which were eliminated by knockout (KO) of the TRPM7 gene using the CRISPR/Cas9 approach or by administration of NS8593 and VER155008, two structurally unrelated inhibitors of the TRPM7 channel. Unlike prior studies with various cell lines showing that TRPM7 KO mutation induces cell growth arrest, we observed that A549 cells maintained normal viability after genetic and pharmacological inactivation of TRPM7. Consequently, we used A549 cells to examine the impact of Cd on cell viability and found that TRPM7 KO mutation and both pharmacological agents mitigated the Cd cytotoxicity. Analogous to A549 cells, electrophysiological analysis of mouse primary alveolar type 2 (ATII) cells revealed endogenous TRPM7 currents and Cd exposure reduced the cell viability of ATII cells in a TRPM7-dependent fashion. Hence, the TRPM7 channel contributes to Cd cytotoxicity in pulmonary cells and can serve as a therapeutic target to alleviate the toxic effects of trace metal exposure.
瞬时受体电位阳离子通道亚家族M成员7（TRPM7）是一种激酶偶联离子通道，在包括肺在内的不同器官的免疫细胞和上皮细胞中表现出高活性。电生理研究表明，TRPM7通道对镁、锌、钙以及微量金属阳离子具有高通透性。虽然TRPM7在镁、锌和钙的细胞平衡中的关键作用已得到充分证明，但其对微量金属阳离子（常见的呼吸道污染物）细胞摄取的贡献仍不清楚。在这里，我们对肺A549细胞进行了电生理评估，发现了内源性TRPM7电流，使用CRISPR/Cas9方法敲除（KO）TRPM7基因或施用NS8593和VER155008（两种结构不相关的TRPM7通道抑制剂）可消除该电流。与之前对各种细胞系的研究不同，那些研究表明TRPM7基因敲除突变会诱导细胞生长停滞，我们观察到TRPM7在基因和药理学失活后，A549细胞仍保持正常活力。因此，我们使用A549细胞来研究镉对细胞活力的影响，发现TRPM7基因敲除突变以及两种药物均可减轻镉的细胞毒性。与A549细胞类似，对小鼠原代肺泡II型（ATII）细胞的电生理分析显示存在内源性TRPM7电流，镉暴露以TRPM7依赖的方式降低了ATII细胞的活力。因此，TRPM7通道在肺细胞中促成了镉的细胞毒性，可作为减轻微量金属暴露毒性作用的治疗靶点。
