Beta-N-methylamino-L-alanine in the presence of bicarbonate is an agonist at non-N-methyl-D-aspartate-type receptors

β-N-Methylamino- l -alanine , a component of the neurotoxic Cycas circinalis plant, activates an ionic current which is antagonized by extracellular Ca 2+ but not by the excitatory amino acid receptor antagonists d,l -2-amino-5-phosphonovalerate (10–100 μM) or 6-cyano-7-nitroquinoxaline-2,3-dione (1–10 μM). This current was reduced by 50% in 0.5 mM extracellular Ca 2+ and 92% in 3.0 mM Ca 2+ when compared to those recorded in 0.1 mM Ca 2+ . Addition of 10 or 20 mM NaHCO 3 to β-N-methylamino- l -alanine (500 μM) potentiated the currents 224% and 578%, respectively. Addition of NaHCO 3 to the extracellular Ringers (pH 7.2) shifted the pH to 7.7 (10 mM) or 8.3 (20 mM). β-N-Methylamino- l -alanine was potentiated by NaHCO 3 at pH 7.2, 7.7 and 8.3, but the potentiation with NaHCO 3 (20 mM) was larger at pH 8.3 (5.7-fold) compared to pH 7.2 (3-fold). NaHCO 3 (20 mM) had no effect on quisqualate-, N-methyl- d -aspartate - or kainate-activated ionic currents. The β-N-methylamino- l -alanine-NaHCO 3 -activated currents were reduced 49% by 1 μM and 80% by 10 μM 6-cyano-7-nitroquinoxaline-2,3-dione suggesting an agonist action at non-N-methyl- d -aspartate-type receptors. Activity at N-methyl- d -aspartate receptors is unlikely since the gb-N-methylamino- l -alanine-NaHCO 3 currents are not antagonized by d,l -2-amino-5-phosphonovalerate (10–100 μM), potentiated by addition of glycine (10 μM) or blocked by extracellular Mg 2+ . These data are consistent with the hypothesis that interaction between β-N-methylamino- l -alanine and bicarbonate produced a new agonist species, which activates quisqualate/kainate-type glutamate receptors and may be responsible for the neurotoxicity of β-N-methylamino- l -alanine in NaHCO 3 solutions. A similar mechanism could describe how normally innocuous amino acids could acquire neurotoxic potential vivo .