title: Chloride-dependent uncoupling of oxidative phosphorylation by triethyllead and triethyltin increases cytosolic free calcium in guinea pig cerebral cortical synaptosomes.
abstract: Metabolically competent isolated cerebral cortical nerve terminals were used to determine the effects of triethyllead (TEL) and triethyltin (TET) on cytosolic free calcium ([Ca2+]c), on plasma and mitochondrial membrane potentials, and on oxidative metabolism. In the presence of physiological concentrations of extracellular ions, 20 microM TEL and 20 microM TET increase [Ca2+]c from 185 nM to 390 and 340 nM, respectively. A simultaneous depolarization of plasma membrane potential (delta psi p) by only 3-4 mV occurs, a drop which is insufficient to open the voltage-sensitive Ca2+ channels. In contrast, an instant and substantial depolarization of mitochondrial membrane potential (delta psi m) upon addition of TEL and TET is evident, as monitored with safranine O fluorescence. At the same concentration, TEL and TET stimulate basal respiration of synaptosomes by 45%, induce oxidation of endogenous NAD(P)H, and reduce the terminal ATP/ADP ratio by 45%. Thus, TEL and TET inhibit ATP production of intrasynaptosomal mitochondria by a mechanism consistent with uncoupling of oxidative phosphorylation. This bioenergetic effect by TEL and TET can be prevented by omitting external chloride, and a concomitant reduction of the increase in [Ca2+]c by about 60% is observed. Uncoupling of mitochondrial ATP synthesis from oxidation by TEL and TET, [corrected] a process that is dependent on external chloride, is the main mechanism by which they [corrected] increase [Ca2+]c.
authors.affiliation: Department of Clinical Neurophysiology, University Central Hospital, Kuopio, Finland.
authors.forename: R A
authors.initials: RA
authors.lastname: Kauppinen
authors.forename: H
authors.initials: H
authors.lastname: Komulainen
authors.forename: H T
authors.initials: HT
authors.lastname: Taipale
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D006168:Guinea Pigs; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D013050:Spectrometry, Fluorescence; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014220:Trialkyltin Compounds / Q000494:pharmacology*; D014267:Triethyltin Compounds / Q000494:pharmacology*
chemical_list: D002712:Chlorides; D009942:Organometallic Compounds; D014220:Trialkyltin Compounds; D014267:Triethyltin Compounds; D009249:NADP; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; C031575:triethyltin; D000244:Adenosine Diphosphate; C010360:triethyllead; D000255:Adenosine Triphosphate; D002118:Calcium