TRPM7 underlies cadmium cytotoxicity in pulmonary cells.

Abstract

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 Mg²⁺, Zn²⁺, and Ca²⁺, as well as trace metal cations. While the critical role of TRPM7 in the cellular balance of Mg²⁺, Zn²⁺, and Ca²⁺ 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 Cd²⁺ on cell viability and found that TRPM7 KO mutation and both pharmacological agents mitigated the Cd²⁺ cytotoxicity. Analogous to A549 cells, electrophysiological analysis of mouse primary alveolar type 2 (ATII) cells revealed endogenous TRPM7 currents and Cd²⁺ exposure reduced the cell viability of ATII cells in a TRPM7-dependent fashion. Hence, the TRPM7 channel contributes to Cd²⁺ cytotoxicity in pulmonary cells and can serve as a therapeutic target to alleviate the toxic effects of trace metal exposure.