GPR17 and GPR52 are activated by the artificial sweeteners sucralose and saccharin

Abstract

G-protein coupled receptors (GPCRs) are a class of transmembrane proteins which are responsible for communication and signalling in a wide variety of cell-cell and cell-environment interactions. They are responsible for senses including smell, sight and taste, in addition to internal metabolite sensing. GPCRs are excellent drug targets due to the important role they play in a variety of physiological processes; over 34% of all FDA approved drugs target GPCRs. Orphan GPCRs are a subset of approximately 90 GPCRs which do not have an established endogenous or exogenous ligand. Artificial sweeteners are a family of organic compounds which activate the GPCR taste receptor (T1R2/T1R3) but are not metabolized by the human body leading to the initial belief that they are safe and effective sugar replacements which reduce caloric consumption. However, recent findings suggest that chronic artificial sweetener consumption may lead to glucose intolerance and metabolic disease and that unknown receptors beyond T1R2/T1R3 are capable of sensing sweet molecules. In this study, 72 family A orphan GPCRs were screened for activation through treatment with a combination of the artificial sweeteners sucralose and saccharin using the PRESTO-Tango resource for GPCR interrogation. The strength of activation in identified receptor candidates was investigated further with both natural and artificial sweeteners. Two receptors were found to be significantly activated by the artificial sweeteners, GPR17 and GPR52, which is the first report of this receptor-agonist pairing. Dose response curves revealed that artificial sweetener activated GPR17 signalling was saturated at a concentration of 2 mM with a 1.5-fold change response for saccharin and a 1.6-fold change response for sucralose relative to control. GPR17 activation was higher for the sucrose treatment with a fold change of 2.1. Conversely, GPR52 responded more strongly to artificial sweeteners with a greater than 5-fold change in receptor activation when treated by sucralose or saccharin but was not activated by sucrose. These findings suggest that these orphan receptors may play a wider role in human metabolism than has been previously considered.