title: The role of NMDA and mGluR5 receptors in calcium mobilization and neurotoxicity of homocysteine in trigeminal and cortical neurons and glial cells.
abstract: Recent studies suggested contribution of homocysteine (HCY) to neurodegenerative disorders and migraine. However, HCY effect in the nociceptive system is essentially unknown. To explore the mechanism of HCY action, we studied short- and long-term effects of this amino acid on rat peripheral and central neurons. HCY induced intracellular Ca²⁺ transients in cultured trigeminal neurons and satellite glial cells (SGC), which were blocked by the NMDA antagonist AP-5 in neurons, but not in SGCs. In contrast, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP), the metabotropic mGluR5 (metabotropic glutamate receptor 5 subtype) antagonist, preferentially inhibited Ca²⁺ transients in SGCs. Prolonged application of HCY induced apoptotic cell death of both kinds of trigeminal cells. The apoptosis was blocked by AP-5 or by the mGluR5 antagonist MTEP. Likewise, in cortical neurons, HCY-induced cell death was inhibited by AP-5 or MTEP. Imaging with 2',7'-dichlorodihydrofluorescein diacetate or mitochondrial dye Rhodamine-123 as well as thiobarbituric acid reactive substances assay did not reveal involvement of oxidative stress in the action of HCY. Thus, elevation of intracellular Ca²⁺ by HCY in neurons is mediated by NMDA and mGluR5 receptors while SGC are activated through the mGluR5 subtype. Long-term neurotoxic effects in peripheral and central neurons involved both receptor types. Our data suggest glutamatergic mechanisms of HCY-induced sensitization and apoptosis of trigeminal nociceptors.
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; Laboratory of Comparative Physiology of Cerebellum, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Science, Saint-Petersburg, Russia.
authors.forename: Polina A
authors.initials: PA
authors.lastname: Abushik
authors.forename: Minna
authors.initials: M
authors.lastname: Niittykoski
authors.forename: Raisa
authors.initials: R
authors.lastname: Giniatullina
authors.forename: Anastasia
authors.initials: A
authors.lastname: Shakirzyanova
authors.forename: Genevieve
authors.initials: G
authors.lastname: Bart
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Fayuk
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Sibarov
authors.forename: Sergei M
authors.initials: SM
authors.lastname: Antonov
authors.forename: Rashid
authors.initials: R
authors.lastname: Giniatullin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006710:Homocysteine / Q000633:toxicity*; D007202:Indicators and Reagents; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins; D010084:Oxidation-Reduction; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014276:Trigeminal Nerve / Q000166:cytology / Q000187:drug effects*
chemical_list: C578937:Grm5 protein, rat; D007202:Indicators and Reagents; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate; D017392:Thiobarbituric Acid Reactive Substances; D006710:Homocysteine; D002118:Calcium
keywords: NMDA receptor; homocysteine; mGluR5; neurodegeneration; pain sensitization; trigeminal ganglion