title: Novel NMDA receptor-specific desensitization/inactivation produced by ingestion of the neurotoxins, β-N-methylamino-L-alanine (BMAA) or β-N-oxalylamino-L-alanine (BOAA/β-ODAP).
abstract: The environmental neurotoxins BMAA (β-N-methylamino-L-alanine) and BOAA (β-N-oxalylamino-L-alanine) are implicated as possible causative agents for the neurodegenerative diseases, amyotrophic lateral sclerosis/ParkinsonismDementia complex (ALS/PDC) and neurolathyrism, respectively. Both are structural analogs of the neurotransmitter, glutamate, and bind postsynaptic glutamate receptors. In this study, the effect of ingestion of these toxins on the response of a singly-innervated, identified, glutamatergic postsynaptic cell in a living, undissected Drosophila is observed by intracellular recording. Previously we have reported that ingested BMAA behaves as an NMDA agonist that produces an abnormal NMDA response in the postsynaptic cell. It is shown here that BOAA also behaves as an NMDA agonist, and produces an effect very similar to that of BMAA on the postsynaptic response. In response to a single stimulus, the amplitude of the NMDA component is decreased, while the time to peak and duration of the NMDA component are greatly increased. No discernable effect on the AMPA component of the response was observed. Furthermore, both BMAA and BOAA cause an NMDAR-specific desensitization in response to repetitive stimulation at the physiological frequency for the postsynaptic cell (5 Hz). The possibility that this phenomenon may represent a response to excessive Ca(2+) entry through NMDAR channels is discussed. This desensitization phenomenon, as well as the abnormal NMDAR gating characteristics induced by BMAA, appears to be rescued during higher frequency stimulation (e.g. 10, 20 Hz).
authors.affiliation: Division of Neurosciences, Beckman Research Institute of the City of Hope Medical Center, 1450 E. Duarte Road, Duarte, CA 91010, USA. Electronic address: jkoenig@coh.org.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Koenig
authors.affiliation: Department of Chemistry, California State University, Fresno. 2555 East San Ramon Ave., MS SB 70, Fresno CA 93740, USA. Electronic address: jgoto@csufresno.edu.
authors.forename: Joy J
authors.initials: JJ
authors.lastname: Goto
authors.affiliation: Division of Neurosciences, Beckman Research Institute of the City of Hope Medical Center, 1450 E. Duarte Road, Duarte, CA 91010, USA. Electronic address: kikeda@coh.org.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000599:Amino Acids, Diamino / Q000633:toxicity*; D000818:Animals; D000087522:Cyanobacteria Toxins; D004331:Drosophila melanogaster / Q000187:drug effects*; D004558:Electric Stimulation; D016202:N-Methylaspartate / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate
chemical_list: D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D016194:Receptors, N-Methyl-D-Aspartate; C001824:beta-N-methylamino-L-alanine; C100126:oxalyldiaminopropionic acid; D016202:N-Methylaspartate
keywords: BMAA; BOAA; Glutamate; NMDA receptor; Neurodegenerative disease; Receptor desensitization