Rokaw M D, West M E, Palevsky P M, Johnson J P
Laboratory of Epithelial Cell Biology, University of Pittsburg Medical Center, Pennsylvania, USA.
Am J Physiol. 1996 Jul;271(1 Pt 1):C194-202. doi: 10.1152/ajpcell.1996.271.1.C194.
The immunosuppressants cyclosporin A (CyA), FK-506, and rapamycin (RAP) have multiple actions on target cells that appear to be mediated by interaction of drug-binding protein complexes. Both FK-506 and CyA, but not RAP, inhibit the Ca2(+)-dependent phosphatase, calcineurin, and in so doing have been found to inhibit Na(+)-K(+)-ATPase activity in various nephron segments. Of interest, FK-506 and RAP, but not CyA, are bound by the steroid receptor-associated FK-506-binding heat shock protein of 56 kDa, HSP56. To determine the physiological effect of this interaction on a steroid-mediated phenomenon, the effect of these agents on steroid-mediated Na+ transport in A6 cells was investigated. Aldosterone stimulation of Na+ transport and Na(+)-K(+)-ATPase activity are significantly inhibited by prolonged incubation with FK-506 and RAP. Although CyA inhibits basal Na(+)-K(+)-ATPase activity, it has no effect on aldosterone-induced Na+ transport or the aldosterone-induced increase in Na(+)-K(+)-ATPase activity. FK-506 inhibits the aldosterone-induced synthesis of G alpha i-3 protein but has no effect on glucocorticoid receptor number as quantified by Western blotting. The results suggest that FK-506 and RAP inhibit steroid-mediated Na+ transport at some pretranslational site. The common interaction of these agents with the steroid receptor-associated HSP56 might account for these findings.
免疫抑制剂环孢素A（CyA）、FK-506和雷帕霉素（RAP）对靶细胞有多种作用，这些作用似乎是由药物结合蛋白复合物的相互作用介导的。FK-506和CyA均可抑制钙依赖性磷酸酶钙调神经磷酸酶，但RAP不能，并且已发现它们在这样做的过程中会抑制不同肾单位节段中的钠钾ATP酶活性。有趣的是，FK-506和RAP可与类固醇受体相关的56 kDa FK-506结合热休克蛋白HSP56结合，但CyA不能。为了确定这种相互作用对类固醇介导现象的生理影响，研究了这些药物对A6细胞中类固醇介导的钠转运的影响。长时间与FK-506和RAP孵育可显著抑制醛固酮对钠转运和钠钾ATP酶活性的刺激作用。虽然CyA抑制基础钠钾ATP酶活性，但它对醛固酮诱导的钠转运或醛固酮诱导的钠钾ATP酶活性增加没有影响。FK-506抑制醛固酮诱导的Gαi-3蛋白合成，但对通过蛋白质印迹法定量的糖皮质激素受体数量没有影响。结果表明，FK-506和RAP在某些翻译前位点抑制类固醇介导的钠转运。这些药物与类固醇受体相关的HSP56的共同相互作用可能解释了这些发现。
