Naturally occurring missense variants of G protein–coupled receptors with loss of function have been linked to metabolic disease in case studies and in animal experiments. The glucagon receptor, one such G protein–coupled receptor, is involved in maintaining blood glucose and amino acid homeostasis; however, loss-of-function mutations of this receptor have not been systematically characterized. Here, we observed fewer glucagon receptor missense variants than expected, as well as lower allele diversity and fewer variants with trait associations as compared with other class B1 receptors. We performed molecular pharmacological phenotyping of 38 missense variants located in the receptor extracellular domain, at the glucagon interface, or with previously suggested clinical implications. These variants were characterized in terms of cAMP accumulation to assess glucagon-induced Gα_s coupling, and of recruitment of β-arrestin-1/2. Fifteen variants were impaired in at least one of these downstream functions, with six variants affected in both cAMP accumulation and β-arrestin-1/2 recruitment. For the eight variants with decreased Gα_s signaling (D63^ECDN, P86^ECDS, V96^ECDE, G125^ECDC, R225^3.30H, R308^5.40W, V368^6.59M, and R378^7.35C) binding experiments revealed preserved glucagon affinity, although with significantly reduced binding capacity. Finally, using the UK Biobank, we found that variants with wildtype-like Gα_s signaling did not associate with metabolic phenotypes, whereas carriers of cAMP accumulation-impairing variants displayed a tendency toward increased risk of obesity and increased body mass and blood pressure. These observations are in line with the essential role of the glucagon system in metabolism and support that Gα_s is the main signaling pathway effecting the physiological roles of the glucagon receptor.

在案例研究和动物实验中，具有功能丧失的 G 蛋白偶联受体的自然发生错义变体与代谢疾病有关。胰高血糖素受体是一种这样的 G 蛋白偶联受体，参与维持血糖和氨基酸稳态。然而，这种受体的功能丧失突变尚未得到系统的表征。在这里，与其他 B1 类受体相比，我们观察到胰高血糖素受体错义变体比预期的要少，等位基因多样性较低，具有性状关联的变体较少。我们对位于受体细胞外结构域、胰高血糖素界面或先前提出的临床意义的 38 个错义变异体进行了分子药理学表型分析。_s耦合，以及 β-arrestin-1/2 的募集。15 个变体在这些下游功能中的至少一个受损，其中 6 个变体在 cAMP 积累和 β-arrestin-1/2 募集中都受到影响。_{对于 Gα s}信号降低的八种变体（D63 ^ECD N、P86 ^ECD S、V96 ^ECD E、G125 ^ECD C、R225 ^3.30 H、 R308 ^5.40 W、V368 ^6.59 M 和 R378 ^7.35 C），结合实验显示胰高血糖素亲和力保留，尽管结合能力显着降低。最后，使用 UK Biobank，我们发现具有类似野生型 Gα _{s 的变体}信号传导与代谢表型无关，而 cAMP 积累损害变异体的携带者显示出肥胖风险增加以及体重和血压增加的趋势。这些观察结果与胰高血糖素系统在代谢中的重要作用一致，并支持 Gα _s是影响胰高血糖素受体生理作用的主要信号通路。