Ruben L, Rasmussen H
Biochim Biophys Acta. 1981 Oct 12;637(3):415-22. doi: 10.1016/0005-2728(81)90046-3.
Phenothiazines and related compounds bind to mitochondrial membranes in approximate proportion to their affinities for calmodulin. Penfluridol (16 microM), pimozide (20 microM), or trifluoperazine (66 microM) completely inhibit ADP-stimulated respiration in isolated rat liver mitochondria, but exert no effect on either uncoupler- or Ca2+-stimulated respiration. The inhibition of ADP-stimulated respiration results from inhibition of the oligomycin-sensitive ATPase. Inhibition of the ATPase does not involve interaction of phenothiazine with calmodulin. The addition of calmodulin with or without calcium to mitochondrial inner membrane preparations has no effect on ATPase activity. The addition of EGTA and the ionophore A23187 prior to the addition of phenothiazine does not prevent the phenothiazine-induced inhibiton of the ATPase. Measurements of inner membrane calmodulin content by gel electrophoresis or cyclic nucleotide phosphodiesterase activation are negative. Despite the absence of calmodulin in the inner membrane preparations, 12.5 nmol trifluoperazine bind per 100 microgram of membrane protein with an association constant, K, of 6.5 . 10(4) M-1. We conclude that calmodulin-binding neuroleptic agents, when added to whole cells, have the potential to disrupt mitochondrial energy production by a reaction which apparently does not involve a phenothiazine-calmodulin interaction.
吩噻嗪类及相关化合物与线粒体膜的结合比例与其对钙调蛋白的亲和力大致成正比。五氟利多（16微摩尔）、匹莫齐特（20微摩尔）或三氟拉嗪（66微摩尔）可完全抑制离体大鼠肝线粒体中由二磷酸腺苷（ADP）刺激的呼吸作用，但对解偶联剂或钙离子刺激的呼吸作用均无影响。ADP刺激的呼吸作用受到抑制是由于寡霉素敏感的ATP酶受到抑制。ATP酶的抑制并不涉及吩噻嗪与钙调蛋白的相互作用。向线粒体内膜制剂中添加有或没有钙离子的钙调蛋白对ATP酶活性均无影响。在添加吩噻嗪之前先添加乙二醇双（2-氨基乙基醚）四乙酸（EGTA）和离子载体A23187并不能阻止吩噻嗪对ATP酶的抑制作用。通过凝胶电泳或环核苷酸磷酸二酯酶激活来测量内膜钙调蛋白含量的结果均为阴性。尽管内膜制剂中不存在钙调蛋白，但每100微克膜蛋白仍可结合12.5纳摩尔三氟拉嗪，其结合常数K为6.5×10⁴ M⁻¹。我们得出结论，当将与钙调蛋白结合的抗精神病药物添加到完整细胞中时，它们有可能通过一种显然不涉及吩噻嗪-钙调蛋白相互作用的反应来破坏线粒体的能量产生。
