Metabolite-sensing G protein-coupled receptors (msGPCRs) (msGPCRs)

Metabolite-sensing G protein-coupled receptors (msGPCRs) represent a specialized class of cell-surface proteins that detect various metabolic intermediates, including free fatty acids, hydroxycarboxylic acids, bile acids, and amino acids [1]. These receptors act as critical sensors that link the nutritional status of the organism to physiological responses, such as the secretion of metabolic hormones like insulin and glucagon-like peptide-1 (GLP-1) [2]. For instance, the free fatty acid receptors (FFARs) like GPR40 and GPR120 play pivotal roles in glucose homeostasis and anti-inflammatory signaling, respectively [3]. In disease states, dysregulation of msGPCR signaling is linked to metabolic disorders such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease, as well as chronic inflammatory conditions [4]. Pharmacological targeting of these receptors, primarily through small-molecule agonists, aims to restore metabolic balance or modulate immune responses, though challenges such as liver toxicity and receptor desensitization have been observed in clinical development [5]. [1] Husted, A. S., et al. (2017). "Metabolite-Sensing G Protein-Coupled Receptors." Cell Metabolism. doi:10.1016/j.cmet.2017.03.008. [2] Offermanns, S. (2014). "Free Fatty Acid (FFA) and Hydroxy Carboxylic Acid (HCA) Receptors." Annual Review of Pharmacology and Toxicology. doi:10.1146/annurev-pharmtox-011613-135945. [3] Ichimura, A., et al. (2014). "Free fatty acid receptors as therapeutic targets." Frontiers in Pharmacology. doi:10.3389/fphar.2014.00236. [4] Davenport, A. P., et al. (2013). "International Union of Basic and Clinical Pharmacology. LXXXVIII." Pharmacological Reviews. doi:10.1124/pr.112.007146. [5] Milligan, G., et al. (2017). "Free fatty acid receptors: emerging targets for treatment of diabetes and metabolic syndrome." Clinical Science. doi:10.1042/CS20160102.

Other names

Nutrient-sensing GPCRsMetabolic GPCRsFree fatty acid receptorsHydroxycarboxylic acid receptorsFFARsHCARs

Agonism of specific receptors within the class to stimulate the release of insulin or incretin hormones (e.g., GPR40, GPR119), or to modulate inflammatory pathways and lipid metabolism (e.g., GPR120, GPR43) [3, 5].