Critically evaluating sweet taste receptor expression and signaling through a molecular pharmacology lens

Abstract

The class C G protein-coupled sweet taste receptor (STR) is responsible for the perception of sweet-tasting molecules. Considered an obligate heterodimer, it consists of taste 1 receptor 2 and taste 1 receptor 3 subunits. Interest in the STR has steadily grown, especially since its discovery in extraoral tissues hints at a metabolic role for the receptor. It is now known that many pharmacologically exploitable binding sites exist across the extracellular and transmembrane regions of both subunits of the STR, indicative of its potential amenability to pharmacotherapeutic modulation. In this review, we briefly describe the structural characteristics and functional relevance of the STR. Then, from a molecular pharmacology perspective, we dissect the research surrounding the regulation of STR surface expression and signal transduction, in both oral and extraoral tissues, and discuss the potential for the exploitation of biased agonists for the STR. We find that despite 20 years of research into the STR, the target remains frustratingly enigmatic. Not only are the mechanisms controlling and regulating the surface expression of the STR unclear, but also research into the full repertoire of signaling partners of the STR is at present inconclusive. Critically, the influence of receptor polymorphisms (including those associated with sugar consumption) on the molecular pharmacology of the receptor remains hitherto unexplored. Finally, we provide recommendations on the reporting of reference sequence identification numbers to avoid incorrect attribution of wildtype to these biologically significant polymorphisms, which we argue may have led to some of the inconsistencies in the field.

The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA1c in a Human Cohort With Variable Levels of Glucose Homeostasis

“…This suggests that heterozygosity is sufficient for the SNP effect on HbA 1c . In contrast, the rs9701796 (Ser9Cys) polymorphism of TAS1R2 , which has comparable allele frequency to Ile191Val ( 17 ), had no associations with HbA 1c ( Table 2 and Figures 1C,D ). No genotype differences were noted in OGTT variables or in insulin sensitivity or pancreatic beta-cell responsiveness during a FSIVGTT ( Table 2 ).…”

“…amino acid) ( 25 ). Out of the nine TAS1R2 nonsynonymous SNPs, the rs35874116 (Ile191Val) and rs9701796 (Cys9Ser) have a minor allele frequency >0.2 and are associated with different nutritional and metabolic variables ( 17 ). TAS1R2 -(Ile191Val) in particular is associated with sugar and carbohydrate consumption in adults ( 11 , 13 ) and in children ( 12 ), but these effects are not due to differences in taste sensitivity ( 26 ).…”

“…We found that TAS1R2-(Val) carriers had reduced HbA 1c , a measure that assesses progression of glycemic burden and predicts diabetic complications. The Ser9Cys substitution is located in the putative signal peptide of TAS1R2 and has been associated with dietary and anthropometric variables in children ( 17 ). However, the Ser9Cys variant did not affect HbA 1c levels or any other assessed variable.…”

The Ile191Val is a partial loss-of-function variant of the TAS1R2 sweet-taste receptor and is associated with reduced glucose excursions in humans

“…Finally, the allele frequencies of most missense variants in the translated region of TAS1R2 are low (<10%), but the rs9701796 allele (Ser9Cys) is comparable to Ile191Val [ 23 ]. This substitution is located in the putative signal peptide of TAS1R2 and has also been associated with dietary and anthropometric variables in children [ 24 ].…”

Saccharin Stimulates Insulin Secretion Dependent on Sweet Taste Receptor-Induced Activation of PLC Signaling Axis

“…Using genetic and pharmacological approaches, we previously showed that fructose potentiates insulin secretion dependent on STR and the activation of a PLC signaling cascade [ 9 ]. However, similar to other GPCRs, there is evidence suggesting that STR may have diverse signaling partners depending on the ligand and cell context [ 10 ]. Therefore, we set to investigate whether saccharin-induced insulin secretion is dependent on STR and elucidate the signaling mechanism.…”