Increased free intrasynaptosomal Ca2+ by neurotoxic organometals: distinctive mechanisms.
Effects of several alkylmetals on free intrasynaptosomal Ca2+ concentration, [Ca2+]i, were studied in vitro using the fluorescent Ca2+ indicator fura-2. Neurotoxic alkylmetals methylmercury (Met-Hg), triethyllead (TEL), triethyltin (TET), and trimethyltin (TMT) (at 2.5-30 microM) increased [Ca2+]i to different degrees. Met-Hg was the most potent, elevating [Ca2+]i 100-800 nM, dose dependently and significantly more than high K+ (150 nM) or veratridine (350 nM). The effect of Met-Hg could not be inhibited with a Ca2+ channel blocker, verapamil, nor with a Na+ channel blocker, tetrodotoxin. Inhibition of the mitochondrial Ca2+ uptake in situ with rotenone + oligomycin decreased the potency of Met-Hg to elevate [Ca2+]i but did not change the resting [Ca2+]i. Met-Hg also slightly decreased synaptosomal ATP. TEL and TET elevated [Ca2+]i by 100-200 nM. The effect of TEL, but not that of TET, could be blocked with verapamil (36%) and veratridine (67%). TEL was less efficient in the presence of ouabain. Neither TEL nor TET had significant mitochondrial effects in situ contributing to [Ca2+]i. TMT increased [Ca2+]i less than TET while dimethyltin and methyltin were inactive. These results indicate that neurotoxic derivatives of alkylmetals studied increase [Ca2+]i. This occurs mainly either by nonspecific increase (Met-Hg, TET) of Ca2+ leakage through the plasma membrane and/or specific interference with the mechanisms regulating Ca2+ fluxes through the plasma membrane (TEL).
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008433:Mathematics; D008767:Methylmercury Compounds / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects; D009840:Oligomycins; D009942:Organometallic Compounds / Q000633:toxicity*; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012402:Rotenone / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D013779:Tetrodotoxin / Q000494:pharmacology; D014220:Trialkyltin Compounds / Q000633:toxicity*; D014267:Triethyltin Compounds / Q000633:toxicity*; D014298:Trimethyltin Compounds / Q000633:toxicity*; D014701:Veratridine / Q000494:pharmacology
D007473:Ion Channels; D008767:Methylmercury Compounds; D009840:Oligomycins; D009942:Organometallic Compounds; D014220:Trialkyltin Compounds; D014267:Triethyltin Compounds; D014298:Trimethyltin Compounds; D012402:Rotenone; C046488:trimethyltin; D013779:Tetrodotoxin; D010042:Ouabain; C031575:triethyltin; C010360:triethyllead; D014701:Veratridine; D000255:Adenosine Triphosphate; D002118:Calcium