The non-nutritive sweetener sucralose increases β-arrestin signaling at the constitutively active orphan G protein-coupled receptor GPR52

Can J Physiol Pharmacol. 2023 Sep 25. doi: 10.1139/cjpp-2023-0199. Online ahead of print.ABSTRACTNon-nutritive sweeteners are popular food additives owing to their low caloric density and powerful sweetness relative to natural sugars. Their lack of metabolism contributes to evidence proclaiming their safety, yet several studies contravene this demonstrating that sweeteners activate sweet taste G protein-coupled receptors (GPCRs) and elicit deleterious metabolic functions through unknown mechanisms. We hypothesize that activation of GPCRs, particularly orphan receptors due to their abundance in metabolically active tissues, contribute to the biological activity of sweeteners. We quantified the response of 64 orphans to the sweeteners saccharin and sucralose using a high-throughput β-arrestin-2 recruitment assay (PRESTO-Tango). GPR52 was the sole receptor that significantly responded to a mixture of sucralose and saccharin. Subsequent experiments revealed sucralose as the activating sweetener. Activation of GPR52 was concentration-dependent, with and EC50 of 0.23 mM, an Emax of 3.43 ± 0.24 fold change at 4 mM. GPR52 constitutively activates CRE pathways; however, we show that sucralose-induced activation of GPR52 does not further activate this pathway. Identification of this novel sucralose-GPCR interaction supports the notion that sucralose elicits off-target signaling through the activation of GPR52, calling into question sucralose's assumed lack of bioactivity.PMID:3774820...
Source: Canadian Journal of Physiology and Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research