Chloride-dependent uncoupling of oxidative phosphorylation by triethyllead and triethyltin increases cytosolic free calcium in guinea pig cerebral cortical synaptosomes.
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.
Kauppinen
R A
RA
Department of Clinical Neurophysiology, University Central Hospital, Kuopio, Finland.
Komulainen
H
H
Taipale
H T
HT
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*
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