Martin F, Bedoya F J
Department of Medical Biochemistry and Molecular Biology, School of Medicine, University of Seville, Spain.
Biochem Pharmacol. 1992 Jul 22;44(2):359-64. doi: 10.1016/0006-2952(92)90020-j.
The role of cyclosporine A (CsA) in cAMP generation and its relationship with guanine nucleotide-binding proteins (G-proteins) was investigated in isolated islets. cAMP accumulation in response to glucose, 3-isobutyl-1-methyl-xanthine (a phosphodiesterase inhibitor) and the calcium ionophore A23187 increased significantly (P less than 0.05) in the presence of 0.5 microgram/mL CsA. CsA (0.5 microgram/mL) was unable to affect the 2.1-fold increase in cAMP formation induced by 30 microM forskolin (an adenylate cyclase complex activator). The pertussis toxin-induced cAMP generation in the presence of 20 mM glucose was suppressed by CsA by 34%. On the other hand, CsA enhanced cAMP levels in cholera toxin-treated islets. CsA caused a non-competitive inhibition of phosphodiesterase activity with half-maximal inhibition at 5 micrograms/mL CsA. CsA blocked the pertussis toxin ADP-ribosylation of a 41-kDa and a 21-kDa islet protein, but not the cholera toxin ADP-ribosylation of a 45-kDa and a 21-kDa islet protein. These data indicate that CsA increases cAMP content by a non-competitive inhibition of phosphodiesterase activity and by acting through G-proteins involved in the modulation of adenylate cyclase activity. An inhibitory effect of CsA on a 21-kDa pertussis toxin-sensitive G-protein was also observed.
在分离的胰岛中研究了环孢素A（CsA）在环磷酸腺苷（cAMP）生成中的作用及其与鸟嘌呤核苷酸结合蛋白（G蛋白）的关系。在存在0.5微克/毫升CsA的情况下，葡萄糖、3 - 异丁基 - 1 - 甲基黄嘌呤（一种磷酸二酯酶抑制剂）和钙离子载体A23187诱导的cAMP积累显著增加（P小于0.05）。CsA（0.5微克/毫升）不能影响30微摩尔福斯可林（一种腺苷酸环化酶复合物激活剂）诱导的cAMP生成增加2.1倍。在20毫摩尔葡萄糖存在下，百日咳毒素诱导的cAMP生成被CsA抑制了34%。另一方面，CsA提高了霍乱毒素处理的胰岛中的cAMP水平。CsA对磷酸二酯酶活性产生非竞争性抑制，在5微克/毫升CsA时达到半数最大抑制。CsA阻断了百日咳毒素对41千道尔顿和21千道尔顿胰岛蛋白的ADP核糖基化，但不影响霍乱毒素对45千道尔顿和21千道尔顿胰岛蛋白的ADP核糖基化。这些数据表明，CsA通过非竞争性抑制磷酸二酯酶活性以及通过参与调节腺苷酸环化酶活性的G蛋白起作用来增加cAMP含量。还观察到CsA对一种21千道尔顿的百日咳毒素敏感G蛋白有抑制作用。
