Inhibition of Mg2+ Extrusion Attenuates Glutamate Excitotoxicity in Cultured Rat Hippocampal Neurons

Abstract

Magnesium plays important roles in the nervous system. An increase in the Mg2+ concentration in cerebrospinal fluid enhances neural functions, while Mg2+ deficiency is implicated in neuronal diseases in the central nervous system. We have previously demonstrated that high concentrations of glutamate induce excitotoxicity and elicit a transient increase in the intracellular concentration of Mg2+ due to the release of Mg2+ from mitochondria, followed by a decrease to below steady-state levels. Since Mg2+ deficiency is involved in neuronal diseases, this decrease presumably affects neuronal survival under excitotoxic conditions. However, the mechanism of the Mg2+ decrease and its effect on the excitotoxicity process have not been elucidated. In this study, we demonstrated that inhibitors of Mg2+ extrusion, quinidine and amiloride, attenuated glutamate excitotoxicity in cultured rat hippocampal neurons. A toxic concentration of glutamate induced both Mg2+ release from mitochondria and Mg2+ extrusion from cytosol, and both quinidine and amiloride suppressed only the extrusion. This resulted in the maintenance of a higher Mg2+ concentration in the cytosol than under steady-state conditions during the ten-minute exposure to glutamate. These inhibitors also attenuated the glutamate-induced depression of cellular energy metabolism. Our data indicate the importance of Mg2+ regulation in neuronal survival under excitotoxicity.

Evidence that OLE RNA is a component of a major stress‐responsive ribonucleoprotein particle in extremophilic bacteria

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Development of Phosphinate Ligand-Based Low-Affinity Ca2+ Fluorescent Probes and Application to Intracellular Ca2+ Imaging

“…In previous studies, it has been demonstrated that glutamate-induced Ca 2+ response leads to depolarization of mitochondrial membrane potential and a decrease in the cellular ATP level. 52 However, the relationship between Ca 2+ levels, mitochondrial membrane potential, and ATP in each neuron has not been well discussed, because simultaneous imaging of those three signals had been difficult. Here, it was achieved by the combined use of KLCA-501 with between CFP and YFP, 32 and TMRE is a mitochondrial membrane potential probe with an orange fluorophore.…”

A Ribosomal Perspective on Neuronal Local Protein Synthesis

“…However, due to the shallow concentration gradient of Mg 2+ across the membrane and the continuous exchange between their bound and the free form in the cytosol, changes in extracellular Mg 2+ availability can severely impact the intracellular Mg 2+ concentration and ribosomal functions. Also, the Mg 2+ deficiency within neurons can be sensed by mTOR signaling that can alter translation in several ways ( Shindo et al, 2020 ).…”