Benishin C G, Krueger B K, Blaustein M P
Department of Physiology, University of Maryland, Baltimore 21201.
Mol Pharmacol. 1988 Feb;33(2):195-201.
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.
钙依赖性、钾刺激的86Rb外流是衡量大鼠脑突触体中钙激活钾电导的指标，它被吩噻嗪类药物和氟哌啶醇所阻断。微摩尔浓度的吩噻嗪类药物氟奋乃静和三氟拉嗪，以及氟哌啶醇（一种非吩噻嗪类抗精神病药物和钙调蛋白拮抗剂）选择性地抑制了钙激活钾通道。这三种药物抑制钙激活钾通道的IC50值约为0.5 - 1微摩尔。对钾刺激的45Ca摄取的测量表明，这些药物对钙激活钾通道的作用并非由于抑制了通过电压门控钙通道的钙内流。舒必利是一种具有弱抗钙调蛋白活性的强效抗精神病药物，是钙激活钾通道相对较弱的抑制剂。氯咪达唑（化合物R - 24571）和W7这两种非吩噻嗪类钙调蛋白拮抗剂并没有选择性地抑制钙激活钾通道。吩噻嗪类药物抑制钙依赖性、钾刺激的86Rb外流的双相剂量反应曲线提示，大鼠脑突触前终末可能存在两种对吩噻嗪类药物敏感性不同的钙激活钾通道。这些结果表明，两种吩噻嗪类药物和氟哌啶醇是神经末梢中钙激活钾通道的强效且相对选择性的抑制剂。这种抑制作用似乎不是由钙调蛋白或多巴胺受体介导的。
