ToxSci Advance Access originally published online on May 12, 2004
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Toxicological Sciences 80, 60-68 (2004)
Toxicological Sciences vol. 80 no. 1 © Society of Toxicology 2004; all rights reserved.
Acute Exposure to Methylmercury Causes Ca2+ Dysregulation and Neuronal Death in Rat Cerebellar Granule Cells through an M3 Muscarinic Receptor-Linked Pathway
Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, and Neuroscience Program, Michigan State University, East Lansing, Michigan 48824
Received March 5, 2004; accepted March 8, 2004
Acute exposure to low concentrations of methylmercury (MeHg) causes a severe loss of intracellular calcium (
) homeostasis, which apparently contributes to neuronal death of cerebellar granule cells in culture. We examined the role of muscarinic receptors in MeHg-induced Ca2+ dysregulation and cell death in rat cerebellar granule cells in vitro using fura-2 single-cell microfluorimetry and viability assays, respectively. The nonspecific muscarinic receptor antagonist atropine significantly delayed the onset of MeHg-induced Ca2+ elevations and reduced the amount of Ca2+ released into the cytosol. Depletion of the smooth endoplasmic reticulum (SER) Ca2+ pool with thapsigargin or down-regulation of muscarinic receptors and inositol-1,3,4-triphosphate (IP3) receptors with bethanechol (BCh) caused similar reductions in the amplitude of the MeHg-induced Ca2+ increase, suggesting that MeHg interacts with muscarinic receptors to cause Ca2+ release from the SER through activation of the IP3 receptors. To determine whether this Ca2+ release plays a role in MeHg-induced cell death, cells were exposed to MeHg in the presence of specific muscarinic receptor inhibitors. Acute exposure to increasing concentrations of MeHg (0.2–1.0 µM) caused a corresponding increase in cell death at 24.5 h post-exposure. Prior down-regulation of muscarinic and IP3 receptors with BCh protected against cell death. Protection was ablated by atropine and the M3 receptor antagonist 4-diphenylacetoxyl-N-methylpiperidine methiodide (DAMP), but not by the neuronal nicotinic receptor antagonist dihydro-ß-erythroidine hydrobromide (DHE). Thus activation of M3 muscarinic receptors with subsequent generation of IP3 evidently contributes to elevated [Ca2+]i and subsequent cytotoxicity of cerebellar granule cells by MeHg.
Key Words: methylmercury; neurotoxicity; inositol-1,4,5-triphosphate receptor; muscarinic receptor; Ca2+-mediated celldeath, cerebellum.
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