Interaction between beta-N-methylamino-L-alanine and excitatory amino acid receptors in brain slices and neuronal cultures.
beta-N-Methylamino-L-alanine (BMAA) stimulated the hydrolysis of polyphosphoinositides (PPI) in hippocampal slices prepared from 8-day old rats. The action of BMAA was antagonized by D,L-2-amino-3-phosphonopropionate (an antagonist of metabotropic receptors) and was largely reduced after lowering the concentration of bicarbonate ions from 25 to 1 mM. In cultured cerebellar neurons, stimulation of PPI hydrolysis by BMAA was mediated by the activation of both metabotropic and N-methyl-D-aspartate (NMDA) receptors. However, BMAA exhibited low activity as an NMDA receptor agonist, as reflected by its low efficacy in increasing cGMP formation in cultures incubated in the absence of extracellular Mg2+. A preferential interaction of BMAA with non-NMDA receptors was confirmed by binding studies on crude synaptic membranes from rat brain. Accordingly, BMAA was more potent in displacing specifically bound [3H]glutamate than 3-(2-carboxypiperazin-4-yl)[1,23H]propyl-1-phosphonic acid (CPP) (a selective NMDA receptor ligand). As expected, the affinity of BMAA for [3H]glutamate or [3H]CPP binding sites was greater in the presence of 25 mM bicarbonate. BMAA weakly displaced specifically bound [3H]glycine in the absence of bicarbonate and, in cultured neurons incubated with buffer containing 1 mM bicarbonate, mimicked glycine in reversing the inhibitory action of kynurenic acid on glutamate-stimulated 45Ca2+ influx. Taken collectively, these results suggest that BMAA acts as a mixed agonist of 'metabotropic' and NMDA receptors.
Copani
A
A
Institute of Pharmacology, University of Catania, Medical School, Italy.
Canonico
P L
PL
Catania
M V
MV
Aronica
E
E
Bruno
V
V
Ratti
E
E
van Amsterdam
F T
FT
Gaviraghi
G
G
Nicoletti
F
F
D000599:Amino Acids, Diamino / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000493:pharmacokinetics; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D000087522:Cyanobacteria Toxins; D006152:Cyclic GMP / Q000096:biosynthesis; D006624:Hippocampus / Q000378:metabolism*; D006868:Hydrolysis; D066298:In Vitro Techniques; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism
D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D009498:Neurotoxins; D010716:Phosphatidylinositols; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; C001824:beta-N-methylamino-L-alanine; D001224:Aspartic Acid; D006152:Cyclic GMP; D002118:Calcium