| 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. | |
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MedLine Citation:
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PMID: 20392940 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Maria Letizia Cucchiaroni; Maria Teresa Viscomi; Giorgio Bernardi; Marco Molinari; Ezia Guatteo; Nicola B Mercuri |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 30 ISSN: 1529-2401 ISO Abbreviation: J. Neurosci. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-15 Completed Date: 2010-05-14 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 5176-88 Citation Subset: IM |
Affiliation:
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Santa Lucia Foundation Istituto di Ricovero e Cura a Carattere Scientifico, 00143 Rome, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Action Potentials
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drug effects,
physiology Amino Acids, Diamino / toxicity* Animals Calcium / metabolism Cell Size / drug effects Cytochromes c / metabolism Dopamine / metabolism* Excitatory Amino Acid Agonists / toxicity* Glutamate Plasma Membrane Transport Proteins / metabolism Membrane Potentials / drug effects, physiology N-Methylaspartate / metabolism Neurons / drug effects*, pathology, physiology Rats Rats, Wistar Reactive Oxygen Species / metabolism Receptors, AMPA / antagonists & inhibitors, metabolism Receptors, Metabotropic Glutamate / metabolism* Substantia Nigra / drug effects*, pathology, physiology Time Factors Transient Receptor Potential Channels / antagonists & inhibitors, metabolism gamma-Aminobutyric Acid / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Amino Acids, Diamino; 0/Excitatory Amino Acid Agonists; 0/Glutamate Plasma Membrane Transport Proteins; 0/Reactive Oxygen Species; 0/Receptors, AMPA; 0/Receptors, Metabotropic Glutamate; 0/Transient Receptor Potential Channels; 0/metabotropic glutamate receptor type 1; 16676-91-8/alpha-amino-beta-methylaminopropionate; 56-12-2/gamma-Aminobutyric Acid; 6384-92-5/N-Methylaspartate; 7440-70-2/Calcium; 9007-43-6/Cytochromes c |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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