Alcohol inhibits the depolarization-induced stimulation of oxidative phosphorylation in synaptosomes.
The effects of alcohol and Ca2+ transport inhibitors on depolarization-induced stimulation of oxidative phosphorylation and free-Ca2+ concentrations in rat synaptosomes were investigated. Glucose oxidation was stimulated by depolarization with K+ or veratridine and by the Ca2+ ionophore ionomycin. The stimulation by K+, veratridine, and ionomycin was correlated with elevation of synaptosomal free Ca2+. Depolarization-stimulated respiration was inhibited by verapamil, Cd2+, and ruthenium red but not by diltiazem. Synaptosomal Ca2+ elevation was inhibited by verapamil but not by ruthenium red. These results indicate that the stimulation depends on elevation of mitochondrial free Ca2+. Ethanol, at pharmacological concentrations (50-200 mM), inhibited the Ca2+-dependent stimulation of oxidative phosphorylation. This inhibition resulted, in part, from the inhibition of voltage-gated Ca2+ channels, which inhibited the elevation of synaptosomal free Ca2+, and, in part, from the stimulation of the mitochondrial Ca2+/Na+ antiporter, which inhibited the elevation of the mitochondrial matrix free Ca2+. The inhibition by ethanol of the excitation-induced stimulation of oxidative phosphorylation in the synapse may contribute to the depressant and narcotic effects of alcohol and enhance excitotoxicity.
Li
H L
HL
Pathology Department, Medical College of Pennsylvania, Philadelphia, USA.
Wu
S
S
Rottenberg
H
H
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects; D004396:Coloring Agents; D004110:Diltiazem / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000201:enzymology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004396:Coloring Agents; D007476:Ionophores; D002104:Cadmium; D012430:Ruthenium Red; D000431:Ethanol; D015759:Ionomycin; D011189:Potassium Chloride; D014701:Veratridine; D000255:Adenosine Triphosphate; D014700:Verapamil; D004110:Diltiazem; D005947:Glucose; D002118:Calcium