Alvarez J, Montero M, Garcia-Sancho J
Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Spain.
FASEB J. 1992 Jan 6;6(2):786-92. doi: 10.1096/fasebj.6.2.1537469.
The filling state of the intracellular Ca2+ stores of rat thymocytes regulates plasma membrane permeability to Mn2+, used here as a Ca2+ surrogate for plasma membrane Ca2+ channels. Emptying of the Ca2+ stores accelerated Mn2+ entry about 10-fold, and refilling with Ca2+ restored low Mn2+ permeability. The acceleration of Mn2+ entry observed in cells with empty intracellular Ca2+ stores was prevented by cytochrome P450 inhibitors. Imidazole antimycotics, especially econazole and miconazole, were the most potent inhibitors (IC50 approximately equal to 10(-6) M). The inhibitor sensitivity profile was similar to IA-type cytochrome P450. Calmodulin antagonists increased the plasma membrane permeability to Mn2+ in cells with filled Ca2+ stores, and this effect was also blocked by imidazole antimycotics. On this basis, we propose a model in which activation of a cytochrome P450, situated at the Ca2+ stores, opens a plasma membrane Ca2+ pathway. This activity would be inhibited by Ca2+ inside the stores by a calmodulin-dependent mechanism.
大鼠胸腺细胞内钙离子储存的充盈状态调节质膜对锰离子的通透性，本文将锰离子用作质膜钙离子通道的钙离子替代物。钙离子储存排空使锰离子进入速度加快约10倍，而重新充盈钙离子则恢复低锰离子通透性。细胞色素P450抑制剂可阻止胞内钙离子储存排空的细胞中观察到的锰离子进入加速现象。咪唑类抗真菌药，尤其是益康唑和咪康唑，是最有效的抑制剂（半数抑制浓度约为10⁻⁶M）。抑制剂敏感性谱与IA型细胞色素P450相似。钙调蛋白拮抗剂增加了钙离子储存充盈的细胞中质膜对锰离子的通透性，且该效应也被咪唑类抗真菌药阻断。在此基础上，我们提出一个模型，即位于钙离子储存处的细胞色素P450激活后会打开质膜钙离子通道。该活性会被储存内的钙离子通过钙调蛋白依赖机制抑制。
