Dantrolene antagonizes the glycineB site of the NMDA receptor

In this study we tested the hypothesis that dantrolene, an established inhibitor of the skeletal muscle isoform of the ryanodine receptor, may interfere with activity of NMDA receptors in neurons. We assessed the effects of dantrolene on [3H]MK-801 and [3H]glycine binding to isolated rat cortical membranes. Dantrolene inhibited [3H]MK-801 binding in the presence of 100 μM NMDA with an IC50 of 58.4 μM. The IC50 value increased to 99.6, 343.0 and 364.6 μM in the presence of 10, 30 and 50 μM glycine, respectively, suggesting that dantrolene competes with glycine for binding site at the NMDA receptor complex. A binding assay using [3H]glycine confirmed this supposition: dantrolene inhibited strychnine-insensitive glycine binding in a dose-dependent way. Thus, our results show that dantrolene at concentrations of 50–100 μM and higher blocks the glycine binding site of the NMDA receptor complex and in this way inhibits activation of the NMDA ion channel. These data reveal a new mechanism of dantrolene action in neuronal tissue. Our results also suggest that the neuroprotective effect of dantrolene may be at least partly explained by its activity as a non-competitive antagonist of NMDA receptors.