BETA-N-METHYLAMINO-L-ALANINE IN THE PRESENCE OF BICARBONATE IS AN AGONIST AT NON-N-METHYL-D-ASPARTATE-TYPE RECEPTORS

Beta-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 muM) or 6-cyano-7-nitroquinoxaline-2,3-dione (1-10 muM). 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 beta-N-methylamino-L-alanine (500 muM) 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). Beta-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 pH8.3 (5.7-fold) compared to pH7.2 (3-fold). NaHCO3 (20 mM) had no effect on quisqualate-, N-methyl-D-aspartate- or kainate-activated ionic currents. The beta-N-methylamino-L-alanine-NaHCO3-activated currents were reduced 49% by 1 muM and 80% by 10 muM 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 beta-N-methylamino-L-alanine-NaHCO3 currents are not antagonized by D,L-2-amino-5-phosphonovalerate (10-100 muM), potentiated by addition of glycine (10 muM) or blocked by extracellular Mg2+. These data are consistent with the hypothesis that interaction between beta-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 beta-N-methylamino-L-alanine in NaHCO3 solutions. A similar mechanism could describe how normally innocuous amino acids could acquire neurotoxic potential in vivo.