Glucagon signaling in metabolic regulation

Glucagon and insulin are peptide hormones released from the pancreas into the blood, that normally act in complementary fashion to stabilize blood glucose concentration. When blood glucose levels rise, insulin release stimulates glucose uptake from the blood, glucose breakdown (glycolysis), and glucose storage as glycogen. When blood glucose levels fall, glucagon release stimulates glycogen breakdown and de novo glucose synthesis (gluconeogenesis), while inhibiting glycolysis and glycogen synthesis.<br>At a molecular level, the binding of glucagon to the extracellular face of its receptor causes conformational changes in the receptor that allow the dissociation and activation of subunits Gs and Gq. The activation of Gq leads to the activation of phospholipase C, production of inositol 1,4,5-triphosphate, and subsequent release of intracellular calcium. The activation of Gs leads to activation of adenylate cyclase, an increase in intracellular cAMP levels, and activation of protein kinase A (PKA). Active PKA phosphorylates key enzymes of glycogenolysis, glycogenesis, gluconeogenesis, and glycolysis, modifying their activities. These signal transduction events, and some of their downstream consequences, are illustrated below (adapted from Jiang and Zhang, 2003).

胰高血糖素和胰岛素是由胰腺分泌至血液中的肽类激素，它们通常以互补的方式作用，以稳定血糖浓度。当血糖水平上升时，胰岛素的释放刺激葡萄糖从血液中的摄取、葡萄糖的分解（糖酵解）以及葡萄糖以糖原的形式储存。当血糖水平下降时，胰高血糖素的释放刺激糖原的分解和新生葡萄糖的合成（糖异生），同时抑制糖酵解和糖原的合成。在分子层面上，胰高血糖素与其受体的细胞外表面结合导致受体构象变化，从而允许亚基Gs和Gq的解离和激活。Gq的激活导致磷脂酶C的激活，产生肌醇1,4,5-三磷酸，并随后释放细胞内钙。Gs的激活导致腺苷酸环化酶的激活，细胞内cAMP水平的增加，以及蛋白激酶A（PKA）的激活。活跃的PKA磷酸化糖原分解、糖原合成、糖异生和糖酵解的关键酶，从而调节其活性。以下示意图展示了这些信号转导事件及其部分下游效应（改编自Jiang和Zhang，2003年）。