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Acute exposure to methylmercury causes Ca2+ dysregulation and neuronal death in rat cerebellar granule cells through an M3 muscarinic receptor-linked pathway.

Authors: Limke, TL  Bearss, JJ  Atchison, WD 
Citation: Limke TL, etal., Toxicol Sci. 2004 Jul;80(1):60-8. Epub 2004 May 12.
Pubmed: (View Article at PubMed) PMID:15141107
DOI: Full-text: DOI:10.1093/toxsci/kfh131

Acute exposure to low concentrations of methylmercury (MeHg) causes a severe loss of intracellular calcium (Ca2+(i)) 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 microM) caused a corresponding increase in cell death at 24.5 h post-exposure. Prior down-regulation of muscarinic and IP3receptors 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-beta-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.


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CRRD Object Information
CRRD ID: 2303392
Created: 2009-02-10
Species: All species
Last Modified: 2009-02-10
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.