Ammon H P, Heurich R O, Kolb H A, Lang F, Schaich R, Drews G, Leiers T
Department of Pharmacology, University of Tübingen, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Jul;354(2):95-101. doi: 10.1007/BF00178708.
It has been shown that okadaic acid (OA) diminishes insulin secretion of rat pancreatic islets in response to glucose, glyceraldehyde and KCl. Glucose, glyceraldehyde and KCl cause release of insulin by depolarization and subsequent opening of L-type calcium channels. Calcium entry into cells is thought to be related to protein phosphorylation. To evaluate whether or not OA mediated inhibition of insulin secretion in response to depolarization might be due to an interference with calcium uptake, we studied its effect on KCl (30 mM)-induced increases of cytosolic calcium and discharge of insulin in the insulin secreting clonal tumor cell line RINm5F. OA inhibited KCl-stimulated insulin release in concentrations > or = 1 microM. In intact RINm5F cells similar concentrations of OA decreased the activity of protein phosphates PP-1/PP-2A and inhibited the depolarization-induced rise of cytosolic calcium ([Ca2+]i). The latter action could also be achieved with the protein phosphatase inhibitor calyculin A, whereas the OA analogue 1-nor-okadaone, which is without effect on phosphatases, did not affect [Ca2+]i or insulin release. It is concluded that depression of depolarization-induced insulin secretion by OA is due to inhibition of calcium entry along voltage dependent calcium channels. The data also suggest that in RINm5F cells protein phosphatases PP-1/PP-2A are related to the function of voltage-dependent calcium channels.
已表明冈田酸（OA）可减少大鼠胰岛对葡萄糖、甘油醛和氯化钾的胰岛素分泌。葡萄糖、甘油醛和氯化钾通过去极化及随后L型钙通道的开放引起胰岛素释放。钙进入细胞被认为与蛋白质磷酸化有关。为评估OA介导的对去极化反应的胰岛素分泌抑制是否可能归因于对钙摄取的干扰，我们研究了其对胰岛素分泌性克隆肿瘤细胞系RINm5F中30 mM氯化钾诱导的胞质钙增加及胰岛素释放的影响。OA在浓度≥1 μM时抑制氯化钾刺激的胰岛素释放。在完整的RINm5F细胞中，相似浓度的OA降低了蛋白磷酸酶PP-1/PP-2A的活性，并抑制了去极化诱导的胞质钙（[Ca2+]i）升高。蛋白磷酸酶抑制剂花萼海绵诱癌素A也能产生后一种作用，而对磷酸酶无作用的OA类似物1-去甲冈田酸不影响[Ca2+]i或胰岛素释放。结论是，OA对去极化诱导的胰岛素分泌的抑制作用是由于抑制了沿电压依赖性钙通道的钙内流。数据还表明，在RINm5F细胞中，蛋白磷酸酶PP-1/PP-2A与电压依赖性钙通道的功能有关。
