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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

Tobi L. Limke, Jeremy J. Bearss and William D. Atchison1

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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I. Vendrell, M. Carrascal, M.-T. Vilaro, J. Abian, E. Rodriguez-Farre, and C. Sunol
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[Abstract] [PDF]


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