title: An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans.
abstract: 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.
authors.affiliation: Diabetes Research Group, Division of Diabetes & Nutritional Sciences, King's College London School of Medicine, London, UK. stefan.amisten@kcl.ac.uk
authors.forename: Stefan
authors.initials: S
authors.lastname: Amisten
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Peter M
authors.initials: PM
authors.lastname: Jones
authors.forename: Shanta J
authors.initials: SJ
authors.lastname: Persaud
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008024:Ligands; D058990:Molecular Targeted Therapy; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D008024:Ligands; D043562:Receptors, G-Protein-Coupled
keywords: G-protein coupled receptors; GPCR drug targets; GPCRome; Human islets of Langerhans; Islet hormone secretion