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 (K_ATP) 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.

Keywords: G-protein-coupled receptor; gustation; noncaloric sweeteners; sweet taste receptor.

Figure 1

T1R2 + T1R3-dependent and -independent sweet taste signaling pathways. TAS1R2 + TAS1R3 is the primary sweet taste receptor that can bind to all known classes of sweet taste stimuli to activate the inositol 3-phosphate signaling pathway (left). This pathway triggers the release of calcium from the endoplasmic reticulum, which leads to opening of the monovalent cation-selective TRPM5 channel, which causes membrane depolarization by allowing the influx of sodium ions. Depolarization and elevated levels of calcium cause ATP release through the large pore channel formed by CALHM1 and CALHM3. The K_ATP- and SGLT1 pathways, on the other hand, are selective for caloric sugars in the monosaccharide form (right). Complex starch is broken down into maltose by salivary amylase in the mouth. Maltose and other dietary disaccharides such as sucrose are broken down into monosaccharides by maltase and sucrase. Cotransport of sodium and glucose by SGLT1 induces membrane depolarization, while the K_ATP pathway requires catabolism of glucose to generate ATP through glycolysis, tricarboxylic acid cycle, and the electron transport chain, which then inhibits the K_ATP channel, triggering membrane depolarization.

Figure 2

Accessory proteins regulating STR signaling. (A) REEP2 is a chaperone protein that noncovalently interacts with the STR and targets it to the plasma membrane. REEP2 may promote the localization of the STR to lipid rafts, which are thought to be specialized cholesterol and sphingolipid-rich microdomains in the plasma membrane where signaling complexes are assembled. (B) G-protein-interacting proteins regulate G-protein activity by modulating GTP binding or hydrolysis by the Gα subunit. Guanyl nucleotide exchange factors such as R1C8A and RIC8B may promote the exchange of GTP for GDP, thereby activating G-protein signaling, whereas GTPase-activating proteins such as RGS21 activate GTP hydrolysis to terminate G-protein signaling downstream of the STR. Part B adapted with permission from Siderowski and Willard [79].

Figure 3

Leptin and endocannabinoids reciprocally regulate sweet taste signaling. The receptors for leptin and endocannabinoids are expressed in STR-expressing cells. Leptin signaling through the Ob-Rb receptor activates the PI3K–AKT signaling pathway in sweet taste cells to activate the K_ATP channel, thereby reducing the sensitivity of STR-expressing cells. Endocannabinoids signal through the CB1 receptor that is also expressed in these cells, to inhibit adenylyl cyclase, causing cAMP depletion and disinhibition of STR signaling. The action of these and other hormones regulates sweet taste signaling and behavioral responses to sweet tastants.