G-protein coupled receptors (GPCRs) regulate hormone secretion from islets of Langerhans, and recently developed therapies for type-2 diabetes target islet GLP-1 receptors. However, the total number of GPCRs expressed by human islets, as well as their function and interactions with drugs, is poorly understood. In this review we have constructed an atlas of all GPCRs expressed by human islets: the 'islet GPCRome'. We have used this atlas to describe how islet GPCRs interact with their endogenous ligands, regulate islet hormone secretion, and interact with drugs known to target GPCRs, with a focus on drug/receptor interactions that may affect insulin secretion. The islet GPCRome consists of 293 GPCRs, a majority of which have unknown effects on insulin, glucagon and somatostatin secretion. The islet GPCRs are activated by 271 different endogenous ligands, at least 131 of which are present in islet cells. A large signalling redundancy was also found, with 119 ligands activating more than one islet receptor. Islet GPCRs are also the targets of a large number of clinically used drugs, and based on their coupling characteristics and effects on receptor signalling we identified 107 drugs predicted to stimulate and 184 drugs predicted to inhibit insulin secretion. The islet GPCRome highlights knowledge gaps in the current understanding of islet GPCR function, and identifies GPCR/ligand/drug interactions that might affect insulin secretion, which are important for understanding the metabolic side effects of drugs. This approach may aid in the design of new safer therapeutic agents with fewer detrimental effects on islet hormone secretion.

中文翻译：

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人胰岛 G 蛋白偶联受体的图谱和功能分析。

G 蛋白偶联受体 (GPCR) 调节朗格汉斯胰岛的激素分泌，最近开发了针对胰岛 GLP-1 受体的 2 型糖尿病疗法。然而，人类胰岛表达的 GPCRs 的总数，以及它们的功能和与药物的相互作用，却知之甚少。在这篇综述中，我们构建了人类胰岛表达的所有 GPCR 的图谱：“胰岛 GPCRome”。我们使用此图谱描述了胰岛 GPCR 如何与其内源性配体相互作用、调节胰岛激素分泌以及与已知靶向 GPCR 的药物相互作用，重点关注可能影响胰岛素分泌的药物/受体相互作用。胰岛 GPCRome 由 293 个 GPCRs 组成，其中大多数对胰岛素、胰高血糖素和生长抑素分泌的影响未知。胰岛 GPCR 被 271 种不同的内源性配体激活，其中至少 131 种存在于胰岛细胞中。还发现了大量的信号冗余，119 个配体激活了一个以上的胰岛受体。胰岛 GPCR 也是大量临床使用药物的靶点，基于它们的耦合特性和对受体信号传导的影响，我们确定了 107 种预测刺激的药物和 184 种预测抑制胰岛素分泌的药物。胰岛 GPCRome 突出了当前对胰岛 GPCR 功能理解的知识空白，并确定了可能影响胰岛素分泌的 GPCR/配体/药物相互作用，这对于了解药物的代谢副作用很重要。这种方法可能有助于设计新的更安全的治疗剂，对胰岛激素分泌的不利影响较小。