Lönnroth P, Appell K C, Wesslau C, Cushman S W, Simpson I A, Smith U
Department of Medicine II, Sahlgren's Hospital, Gothenburg, Sweden.
J Biol Chem. 1988 Oct 25;263(30):15386-91.
Insulin shifts the steady-state subcellular distribution of insulin-like growth factor II (IGF-II) receptors from a large intracellular pool to the plasma membrane in the rat adipose cell (Wardzala, L. J., Simpson, I. A., Rechler, M. M., and Cushman, S. W. (1984) J. Biol. Chem. 259, 8378-8383). In the present study, the counterregulatory effects of adrenergic stimulation, adenosine deaminase, and cAMP on this process were studied. Both isoproterenol (10(-6) M) and adenosine deaminase reduced insulin sensitivity and also rapidly (t1/2 approximately 1.5 min) decreased the effect of a maximal insulin concentration on the number of cell surface IGF-II receptors by 35-50%, and by 70% when added together. The marked reduction in binding was retained in isolated and solubilized plasma membranes. Both isoproterenol and adenosine deaminase alone increased the EC50 for insulin from 0.06 to 0.17 nM and, when combined, to 0.6 nM. N6-Monobutyryl-cAMP and 8-bromo-cAMP were equally potent in reducing IGF-II binding in the absence of insulin and inhibited maximal insulin-stimulated IGF-II binding by 60 and 30%, respectively. However, only the nonhydrolyzable cAMP analogue, N6-monobutyryl-cAMP, reduced the insulin sensitivity (EC50 0.7 nM). An important stimulatory role for Gi (guanine nucleotide-binding regulatory protein that inhibits adenylate cyclase) was indicated by the altered activities of cells from pertussis toxin-treated animals. The results suggest that beta-adrenergic stimulation through a cAMP-dependent mechanism markedly alters the insulin-stimulated redistribution of IGF-II receptors. This effect is additional to the potent antagonistic action of cAMP on insulin's signalling mechanism.
胰岛素可使大鼠脂肪细胞中胰岛素样生长因子II（IGF-II）受体的稳态亚细胞分布从大量细胞内池转移至质膜（瓦尔扎拉，L. J.，辛普森，I. A.，雷奇勒，M. M.，以及库什曼，S. W.（1984年）《生物化学杂志》259卷，8378 - 8383页）。在本研究中，对肾上腺素能刺激、腺苷脱氨酶和环磷酸腺苷（cAMP）在此过程中的反调节作用进行了研究。异丙肾上腺素（10⁻⁶ M）和腺苷脱氨酶均降低了胰岛素敏感性，并且还迅速（半衰期约1.5分钟）使最大胰岛素浓度对细胞表面IGF-II受体数量的作用降低35 - 50%，两者同时添加时降低70%。结合的显著降低在分离并溶解的质膜中得以保留。单独的异丙肾上腺素和腺苷脱氨酶均使胰岛素的半数有效浓度（EC50）从0.06 nM增至0.17 nM，两者联合时增至0.6 nM。在无胰岛素的情况下，N⁶ - 单丁酰 - cAMP和8 - 溴 - cAMP在降低IGF-II结合方面同样有效，分别抑制最大胰岛素刺激的IGF-II结合60%和30%。然而，只有不可水解的cAMP类似物N⁶ - 单丁酰 - cAMP降低了胰岛素敏感性（EC50为0.7 nM）。百日咳毒素处理动物的细胞活性改变表明了抑制性G蛋白（抑制腺苷酸环化酶的鸟嘌呤核苷酸结合调节蛋白）的重要刺激作用。结果表明，通过cAMP依赖性机制的β - 肾上腺素能刺激显著改变了胰岛素刺激的IGF-II受体再分布。这种作用是除了cAMP对胰岛素信号传导机制的强大拮抗作用之外的。
