Phenothiazines and haloperidol block Ca-activated K channels in rat forebrain synaptosomes.
Ca-dependent, K-stimulated 86Rb efflux, a measure of Ca-activated K conductance in rat brain synaptosomes, was blocked by phenothiazines and haloperidol. Micromolar concentrations of the phenothiazines, fluphenazine and trifluoperazine, and haloperidol, a non-phenothiazine antipsychotic and calmodulin antagonist, selectively inhibited the Ca-activated K channels. The IC50 values of all three agents for inhibition of the Ca-activated K channels was on the order of 0.5-1 microM. Measurements of K-stimulated 45Ca uptake indicated that the effects of these agents on Ca-activated K channels was not due to inhibition of Ca influx through voltage-gated Ca channels. Sulpiride, a potent antipsychotic with weak anti-calmodulin activity, was a relatively weak inhibitor of Ca-activated K channels. Calmidazolium (compound R-24571) and W7, two non-phenothiazine calmodulin antagonists, did not selectively inhibit Ca-activated K channels. Biphasic dose response curves for inhibition of the Ca-dependent, K-stimulated 86Rb efflux by the phenothiazines raise the possibility that there may be two kinds of Ca-activated K channels in rat brain presynaptic terminals, with different sensitivities to the phenothiazines. These results demonstrate that two phenothiazines and haloperidol are potent and relatively selective inhibitors of Ca-activated K channels in nerve endings. This inhibition does not appear to be mediated by calmodulin or by dopamine receptors.
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D010640:Phenothiazines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D011954:Receptors, Dopamine / Q000502:physiology; D013574:Synaptosomes / Q000378:metabolism*
D014150:Antipsychotic Agents; D002147:Calmodulin; D007473:Ion Channels; D010640:Phenothiazines; D011954:Receptors, Dopamine; D006220:Haloperidol; D011188:Potassium; D002118:Calcium