Mechanisms of methylmercury-induced neurotoxicity.
Mercury in both organic and inorganic forms is neurotoxic. Methylmercury (MeHg) is a commonly encountered form of mercury in the environment. Early electrophysiological experiments revealed that MeHg potently affects the release of neurotransmitter from presynaptic nerve terminals. Recently, the hypothesis that these alterations may be mediated by changes in the intracellular concentration of Ca2+ ([Ca2+]i) has been supported. MeHg alters [Ca2+]i by at least two mechanisms. First, it disrupts regulation of Ca2+ from an intracellular Ca2+ pool and second, it increases the permeability of the plasma membrane to Ca2+. MeHg also blocks plasma membrane voltage-dependent Ca2+ and Na+ channels in addition to activating a nonspecific transmembrane cation conductance. Chronic MeHg exposure results in ultrastructural changes and accumulation of MeHg within mitochondria. In vitro, MeHg inhibits several mitochondrial enzymes and depolarizes the mitochondria membrane subsequently reducing ATP production and Ca2+ buffering capacity. Inhibition of protein synthesis is observed after in vivo or in vitro exposures of MeHg and may be an early effect of MeHg. Thus, the early cellular effects of exposure to MeHg are diverse and cell damage likely occurs by more than one mechanism, the effects of which may be additive or synergistic.
Atchison
W D
WD
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824-1317.
Hare
M F
MF
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008767:Methylmercury Compounds / Q000494:pharmacology / Q000506:poisoning / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009422:Nervous System Diseases / Q000139:chemically induced*; D018377:Neurotransmitter Agents / Q000378:metabolism; D014176:Protein Biosynthesis
D007473:Ion Channels; D008767:Methylmercury Compounds; D018377:Neurotransmitter Agents; D002118:Calcium