Wakelam M J, Murphy G J, Hruby V J, Houslay M D
Nature. 1986;323(6083):68-71. doi: 10.1038/323068a0.
The ability of glucagon to stimulate glycogen breakdown in liver played a key part in the classic identification of cyclic AMP and hormonally stimulated adenylate cyclase. But several observations indicate that glucagon can exert effects independent of elevating intracellular cAMP concentrations. These effects are probably mediated by an elevation of the intracellular concentration of free Ca2+ although the mechanism by which this occurs is unknown. We show here that glucagon, at the low concentrations found physiologically, causes both a breakdown of inositol phospholipids and the production of inositol phosphates. Indeed, we show that the glucagon analogue, (1-N-alpha-trinitrophenylhistidine,12-homoarginine)glucagon (TH-glucagon), which does not activate adenylate cyclase or cause any increase in cAMP in hepatocytes yet can fully stimulate glycogenolysis, gluconeogenesis and urea synthesis, stimulates the production of inositol phosphates. This stimulation of inositol phospholipid metabolism by low concentrations of glucagon provides a mechanism whereby glucagon can exert cAMP-independent actions on target cells. We suggest that hepatocytes possess two distinct receptors for glucagon, a GR-1 receptor coupled to stimulate inositol phospholipid breakdown and a GR-2 receptor coupled to stimulate adenylate cyclase activity.
胰高血糖素刺激肝脏糖原分解的能力在环磷酸腺苷（cAMP）和激素刺激的腺苷酸环化酶的经典鉴定中起到了关键作用。但多项观察结果表明，胰高血糖素可以发挥独立于提高细胞内cAMP浓度的作用。这些作用可能是由细胞内游离Ca2+浓度升高介导的，尽管其发生机制尚不清楚。我们在此表明，在生理发现的低浓度下，胰高血糖素会导致肌醇磷脂的分解和肌醇磷酸的产生。事实上，我们表明胰高血糖素类似物（1-N-α-三硝基苯基组氨酸，12-高精氨酸）胰高血糖素（TH-胰高血糖素），它不会激活腺苷酸环化酶或导致肝细胞中cAMP有任何增加，但却能充分刺激糖原分解、糖异生和尿素合成，它能刺激肌醇磷酸的产生。低浓度胰高血糖素对肌醇磷脂代谢的这种刺激提供了一种机制，通过该机制胰高血糖素可以对靶细胞发挥不依赖cAMP的作用。我们认为肝细胞拥有两种不同的胰高血糖素受体，一种GR-1受体与刺激肌醇磷脂分解偶联，另一种GR-2受体与刺激腺苷酸环化酶活性偶联。
