Doi R, Inoue K, Chowdhury P, Rayford P L
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock.
J Pharmacol Exp Ther. 1993 Feb;264(2):873-8.
We examined the effects of FK506 on amylase secretion and intracellular pathway in stimulus secretion coupling in isolated pancreatic acini. Amylase release from isolated acini in response to cholecystokinin octapeptide (CCK-8) was suppressed by exposing acini to FK506. The suppressing effect of FK506 on amylase release from acini was dependent on the concentration of FK506 and the time of exposure to FK506. Amylase releases in response to 8-bromo-cAMP and vasoactive intestinal peptide and phorbol ester (12-O-tetradecanoylphorbol 13-acetate) were not suppressed when acini were exposed to FK506, suggesting that the cAMP-dependent protein kinase pathway and protein kinase C pathway were not affected by FK506. However, amylase release in response to calcium ionophore (4-bromo-A23187) was suppressed by FK506, whereas the increase in cytosolic free calcium concentration caused by 4-bromo-A23187 was not affected by FK506. These results suggest that FK506 suppressed secretagogue-stimulated amylase release in acini by altering Ca(++)-mediated intracellular pathways. Further, the property of CCK-8 binding site, CCK-8 stimulated inositol phosphates formation, rises in cytosolic free calcium concentration, and calcium efflux from acini were not suppressed by exposing acini to FK506. These findings indicate that FK506 suppresses amylase release by affecting postreceptor intracellular pathways that are mediated by Ca++ in stimulus secretion coupling.
我们研究了FK506对分离的胰腺腺泡刺激分泌偶联过程中淀粉酶分泌及细胞内信号通路的影响。将腺泡暴露于FK506可抑制分离的腺泡对八肽胆囊收缩素（CCK-8）的反应而释放淀粉酶。FK506对腺泡淀粉酶释放的抑制作用取决于FK506的浓度及暴露时间。当腺泡暴露于FK506时，对8-溴-cAMP、血管活性肠肽和佛波酯（12-O-十四酰佛波醇13-乙酸酯）的反应所导致的淀粉酶释放未受抑制，这表明cAMP依赖性蛋白激酶途径和蛋白激酶C途径不受FK506影响。然而，FK506可抑制对钙离子载体（4-溴-A23187）的反应所导致的淀粉酶释放，而4-溴-A23187所引起的胞质游离钙浓度升高不受FK506影响。这些结果表明，FK506通过改变Ca(++)介导的细胞内信号通路来抑制腺泡中促分泌剂刺激的淀粉酶释放。此外，将腺泡暴露于FK506不会抑制CCK-8结合位点的特性、CCK-8刺激的肌醇磷酸形成、胞质游离钙浓度升高以及腺泡中的钙外流。这些发现表明，FK506通过影响刺激分泌偶联中由Ca++介导的受体后细胞内信号通路来抑制淀粉酶释放。
