Magnesium-Induced Cell Survival Is Dependent on TRPM7 Expression and Function

Mg²⁺ homeostasis is essential for cell survival and the loss of this regulation has been associated with many neurodegenerative diseases, including loss of dopaminergic neurons. Although the neurotoxin-mediated loss of dopaminergic neurons in Parkinson disease models is extensively studied, the ion channel(s) that regulate Mg²⁺ homeostasis and thus could prevent neuronal cell death is not yet identified. Here, we show that TRPM7 (transient receptor potential melastatin 7) is involved in regulating Mg²⁺ homeostasis in dopaminergic cells. Importantly, transient loss of TRPM7 decreased intracellular Mg²⁺ levels and decreased dopaminergic cells/neurons survival. We provide further evidence that both increases in extracellular Mg²⁺ or transiently increasing TRPM7 levels protected dopaminergic SH-SY5Y cells against neurotoxin-mediated cell death. Neurotoxin treatment significantly decreased TRPM7 levels in both SH-SY5Y cells and the substantia nigra pars compacta region of mice, along with a decrease in Mg²⁺ influx. Moreover, Mg²⁺ supplementation showed a concentration-dependent decrease in caspase-3 activity, an increase in cell survival, restored mitochondrial membrane potential, and increase TRPM7 levels in neurotoxin-treated cells. In contrast, transient silencing of TRPM7 inhibited the positive effect of Mg²⁺ supplementation in protecting against neurotoxins. Whereas, TRPM7 overexpression not only maintained Mg²⁺ homeostasis but also inhibited caspase 3 activity that induced cell survival. Overall, these results suggest a significant role of TRPM7 channels in Mg²⁺ homeostasis and the survival of neurotoxin-induced loss of dopaminergic cells.