Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the development of new classes of therapeutic agents targeting glucagon release, key α-cell signaling pathways that regulate glucagon secretion need to be identified. Here, we focused on the potential importance of α-cell G_s signaling on modulating α-cell function. Studies with α-cell-specific mouse models showed that activation of α-cell G_s signaling causes a marked increase in glucagon secretion. We also found that intra-islet adenosine plays an unexpected autocrine/paracrine role in promoting glucagon release via activation of α−cell G_s-coupled A_2A adenosine receptors. Studies with α-cell-specific Gα_s knockout mice showed that α-cell G_s also plays an essential role in stimulating the activity of the Gcg gene, thus ensuring proper islet glucagon content. Our data suggest that α-cell enriched G_s-coupled receptors represent potential targets for modulating α-cell function for therapeutic purposes.

胰高血糖素是一种从胰腺α细胞释放的激素，对于维持血糖正常至关重要，并在糖尿病的病理生理学中起关键作用。为了刺激针对胰高血糖素释放的新型治疗剂的开发，需要确定调节胰高血糖素分泌的关键α细胞信号通路。在这里，我们重点研究了 α 细胞 G_s 信号传导对调节 α 细胞功能的潜在重要性。对 α 细胞特异性小鼠模型的研究表明，α细胞 G_s 信号转导的激活导致胰高血糖素分泌的显着增加。我们还发现胰岛内腺苷通过激活 α 细胞 G_s 偶联的 A_2A 腺苷受体在促进胰高血糖素释放中发挥意想不到的自分泌/旁分泌作用。对 α 细胞特异性 Gα_s 敲除小鼠的研究表明，α 细胞 G_s 在刺激 Gcg 基因的活性方面也起着重要作用，从而确保适当的胰岛胰高血糖素含量。我们的数据表明，富含 α 细胞的 G_s 偶联受体代表了出于治疗目的调节 α 细胞功能的潜在靶标。