The effects of ethanol on different sarco/endoplasmic reticulum Ca(2+)-transport ATPases (SERCAs) were studied. In sarcoplasmic reticulum vesicles, ethanol concentrations varying from 5 to 20% promoted a progressive inhibition of Ca2+ uptake, enhancement of Ca2+ efflux, activation of the ATPase activity, increase of the enzyme phosphorylation by ATP and inhibition of enzyme phosphorylation by P1. The effects of ethanol on Ca2+ uptake and Ca2+ efflux were antagonized by Mg2+, P(i) and spermine. The increased efflux promoted by ethanol was antagonized by Ca2+ and thapsigargin. In brain and platelet vesicles a biphasic effect of ethanol was observed, so that activation occurred at low concentrations (5-10%) and inhibition at higher concentrations. The activation was not observed with the use of n-propanol and n-butanol. Different from the situation in sarcoplasmic reticulum, the decrease of the Ca2+ uptake in brain and platelet vesicles was associated with an inhibition of the ATPase activity. Mg2+ and P(i) antagonized the enhancement of Ca2+ efflux and the inhibition of Ca2+ uptake promoted by ethanol. However, thapsigargin and Ca2+ did not arrest the Ca2+ efflux promoted by ethanol in brain and platelet preparations. These results suggest that, in sarcoplasmic reticulum vesicles, ethanol uncouples the pump, promoting its activity as a Ca2+ channel. The SERCA isoform found in skeletal muscle has different properties from the isoforms found in brain and blood platelets.