Disruption of intraneuronal divalent cation regulation by methylmercury: are specific targets involved in altered neuronal development and cytotoxicity in methylmercury poisoning?
Methylmercury is an environmental contaminant which causes relatively specific degeneration of the granular layer of the cerebellum, despite its ability to bind thiol groups in proteins of all cell types. The mechanisms underlying the specific targeting of cells during MeHg poisoning may depend on specific receptors and other targets related to divalent cation homeostasis, particularly intracellular calcium (Ca(2+)(i) signaling. MeHg disrupts Ca(2+)(i) homeostasis in a number of neuronal models, including cerebellar granule cells in primary culture, and contributes to MeHg-induced cell death, impaired synaptic function and disruption of neuronal development. Interestingly, the disruption of [Ca(2+)](i) regulation occurs through specific pathways which affect Ca(2+) regulation by organelles, particularly mitochondria and the smooth endoplasmic reticulum (SER). Cholinergic pathways which affect [Ca(2+)](i) signaling also appear to be critical targets, particularly muscarinic acetylcholine (ACh) receptors which are linked to Ca(2+) release through inositol-1,4,5-triphosphate (IP(3)) receptors. [Ca(2+)](i) dysregulation may also underlie observed alterations in cerebellar neuron development through interaction with specific target(s) in the developing axon. In this review, we examine the hypothesis that MeHg affects specific targets to cause disruption of neuronal development and cell death.
Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, Michigan State University, B-331 Life Sciences Building, East Lansing, MI 48824-1317, USA.
Tobi L
TL
Limke
Steven R
SR
Heidemann
William D
WD
Atchison
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000502:physiology; D002413:Cations, Divalent / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D008630:Mercury Poisoning / Q000503:physiopathology*; D008767:Methylmercury Compounds / Q000494:pharmacology* / Q000506:poisoning*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
D002413:Cations, Divalent; D008767:Methylmercury Compounds; D002118:Calcium