Sweet Taste Signaling: The Core Pathways and Regulatory Mechanisms

Abstract

Sweet taste, a proxy for sugar-derived calories, is an important driver of food intake, and animals have evolved robust molecular and cellular machinery for sweet taste signaling. The overconsumption of sugar-derived calories is a major driver of obesity and other metabolic diseases. A fine-grained appreciation of the dynamic regulation of sweet taste signaling mechanisms will be required for designing novel noncaloric sweeteners with better hedonic and metabolic profiles and improved consumer acceptance. Sweet taste receptor cells express at least two signaling pathways, one mediated by a heterodimeric G-protein coupled receptor encoded by taste 1 receptor members 2 and 3 (TAS1R2 + TAS1R3) genes and another by glucose transporters and the ATP-gated potassium (KATP) channel. Despite these important discoveries, we do not fully understand the mechanisms regulating sweet taste signaling. We will introduce the core components of the above sweet taste signaling pathways and the rationale for having multiple pathways for detecting sweet tastants. We will then highlight the roles of key regulators of the sweet taste signaling pathways, including downstream signal transduction pathway components expressed in sweet taste receptor cells and hormones and other signaling molecules such as leptin and endocannabinoids.

Interkingdom Detection of Bacterial Quorum-Sensing Molecules by Mammalian Taste Receptors

“…T1R receptors are encoded by TAS1R genes. T1Rs form sweet and umami receptors, thought to be “pleasant” tastes because they signal the presence of beneficial nutrients in foods [ 38 , 67 ]. The sweet receptor is formed from a heterodimer of T1R2 and T1R3 (T1R2/3), while the umami receptor is created by heterodimerization of T1R1 and T1R3 (T1R1/3) [ 38 , 67 ].…”

“…T1Rs form sweet and umami receptors, thought to be “pleasant” tastes because they signal the presence of beneficial nutrients in foods [ 38 , 67 ]. The sweet receptor is formed from a heterodimer of T1R2 and T1R3 (T1R2/3), while the umami receptor is created by heterodimerization of T1R1 and T1R3 (T1R1/3) [ 38 , 67 ]. T1Rs are class C GPCRs with N-terminal “Venus fly trap” domains containing binding sites for multiple structurally-diverse agonists [ 68 ].…”

“…Moreover, many plant compounds are also bitter [ 179 , 280 , 281 , 282 , 283 , 284 ], and activation of T2Rs may explain particular beneficial effects with some homeopathic plant-based therapies. The drive to develop artificial non-metabolizable sweeteners has also led to many compounds known to activate the sweet taste receptor that might also be leveraged therapeutically [ 38 , 67 ].…”

Tas1R3 Dependent and Independent Recognition of Sugars in the Urethra and the Role of Tuft Cells in this Process

“…Here, a heterodimer of taste receptor type 1 member 3 and 2 (Tas1R3; Tas1R2) forms a sweet taste receptor [17,18] and downstream signaling occurs though taste-specific G protein 𝛼gustducin (GNAT3), phospholipase C𝛽2 (PLC𝛽2) and the transient potential receptor cation channel subfamily M (melanostatin) member 5 (TRPM5), all commonly known to be part of the canonical taste transduction cascade. [17,19,20] Mice lacking Tas1R3 show a reduced preference for sucrose and saccharin in behavioral assays. [21] Additionally, a Tas1R3 independent sweet detection pathway has been discovered.…”

“…[22][23][24] Involving the sodium/glucose-cotransporter (sodium-glucose linked transporter; SGLTs), in particular SGLT1, [24] or glucose-transporters (GLUTs) as well as brush border enzymes and ATP-sensitive K + channels (K ATP ) play a crucial role in this pathway. [20,22,23] Monitoring the luminal content in various organs to identify potential threats is an integral function of the innate immune system. One type of sentinel cells that take on this task are specialized epithelial cells called tuft-, brush-or chemosensory cells.…”