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Chloride‐Dependent Uncoupling of Oxidative Phosphorylation by Triethyllead and Triethyltin Increases Cytosolic Free Calcium in Guinea Pig Cerebral Cortical Synaptosomes
Author(s) -
Kauppinen Risto A.,
Komulainen Hannu,
Taipale Hannu T.
Publication year - 1988
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1988.tb01132.x
Subject(s) - chemistry , oxidative phosphorylation , depolarization , synaptosome , mitochondrion , calcium , membrane potential , adenosine triphosphate , nad+ kinase , biophysics , biochemistry , bioenergetics , membrane , biology , enzyme , organic chemistry
Metabolically competent isolated cerebral cortical nerve terminals were used to determine the effects of triethyllead (TEL) and triethyltin (TET) on cytosolic free calcium ([Ca 2+ ] c ), on plasma and mitochondrial membrane potentials, and on oxidative metabolism. In the presence of physiological concentrations of extracellular ions, 20 μ M TEL and 20 μ M TET increase [Ca 2+ ] c from 185 n M to 390 and 340 n M , respectively. A simultaneous depolarization of plasma membrane potential (ΔΨ p ) by only 3–4 mV occurs, a drop which is insufficient to open the voltage‐sensitive Ca 2+ channels. In contrast, an instant and substantial depolarization of mitochondrial membrane potential (ΔΨ p ) upon addition of TEL and TET is evident, as monitored with saf‐ranine 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 [Ca 2+ ] c by about 60% is observed. Uncoupling of mitochondrial ATP synthesis from oxidation, a process that is dependent on external chloride, is the main mechanism by which TEL and TET increase [Ca 2+ ] c .