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

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 wild-type to these biologically significant polymorphisms, which we argue may have led to some of the inconsistencies in the field.