Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative beta-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons.
Amyotrophic lateral sclerosis-Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, and Alzheimer's symptoms that is prevalent in the Guam population. beta-N-Methylamino alanine (BMAA) has been proposed as the toxic agent damaging several neuronal types in ALS-PDC, including substantia nigra pars compacta dopaminergic (SNpc DAergic) neurons. BMAA is a mixed glutamate receptor agonist, but the specific pathways activated in DAergic neurons are not yet known. We combined electrophysiology, microfluorometry, and confocal microscopy analysis to monitor membrane potential/current, cytosolic calcium concentration ([Ca(2+)](i)) changes, cytochrome-c (cyt-c) immunoreactivity, and reactive oxygen species (ROS) production induced by BMAA. Rapid toxin applications caused reversible membrane depolarization/inward current and increase of firing rate and [Ca(2+)](i) in DAergic neurons. The inward current (I(BMAA)) was mainly mediated by activation of metabotropic glutamate receptor 1 (mGluR1), coupled to transient receptor potential (TRP) channels, and to a lesser extent, AMPA receptors. Indeed, mGluR1 (CPCCOEt) and TRP channels (SKF 96365; Ruthenium Red) antagonists reduced I(BMAA), and a small component of I(BMAA) was reduced by the AMPA receptor antagonist CNQX. Calcium accumulation was mediated by mGluR1 but not by AMPA receptors. Application of a low concentration of NMDA potentiated the BMAA-mediated calcium increase. Prolonged exposure to BMAA caused significant modifications of membrane properties, calcium overload, cell shrinkage, massive cyt-c release into the cytosol and ROS production. In SNpc GABAergic neurons, BMAA activated only AMPA receptors. Our study identifies the mGluR1-activated mechanism induced by BMAA that may cause the neuronal degeneration and parkinsonian symptoms seen in ALS-PDC. Moreover, environmental exposure to BMAA might possibly also contribute to idiopathic PD.
Cucchiaroni
Maria Letizia
ML
Santa Lucia Foundation Istituto di Ricovero e Cura a Carattere Scientifico, 00143 Rome, Italy.
Viscomi
Maria Teresa
MT
Bernardi
Giorgio
G
Molinari
Marco
M
Guatteo
Ezia
E
Mercuri
Nicola B
NB
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000599:Amino Acids, Diamino / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D000087522:Cyanobacteria Toxins; D045304:Cytochromes c / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D013997:Time Factors; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D018690:Excitatory Amino Acid Agonists; D050491:Glutamate Plasma Membrane Transport Proteins; D017382:Reactive Oxygen Species; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D050051:Transient Receptor Potential Channels; C104077:metabotropic glutamate receptor type 1; C001824:beta-N-methylamino-L-alanine; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D045304:Cytochromes c; D002118:Calcium; D004298:Dopamine
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