β-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 Ca²⁺ 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 Ca²⁺ and 92% in 3.0 mM Ca²⁺ when compared to those recorded in 0.1 mM Ca²⁺. Addition of 10 or 20 mM NaHCO₃ to β-N-methylamino-l-alanine (500 μM) potentiated the currents 224% and 578%, respectively. Addition of NaHCO₃ 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 NaHCO₃ at pH 7.2, 7.7 and 8.3, but the potentiation with NaHCO₃ (20 mM) was larger at pH 8.3 (5.7-fold) compared to pH 7.2 (3-fold). NaHCO₃ (20 mM) had no effect on quisqualate-, N-methyl-d-aspartate- or kainate-activated ionic currents. The β-N-methylamino-l-alanine-NaHCO₃-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-NaHCO₃ 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 Mg²⁺. 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 NaHCO₃ solutions. A similar mechanism could describe how normally innocuous amino acids could acquire neurotoxic potential _vivo.