Functional roles of the sweet taste receptor in oral and extraoral tissues

Abstract

Purpose of review: This review summarizes and discusses the current knowledge about the physiological roles of the sweet taste receptor in oral and extraoral tissues.

Recent findings: The expression of a functional sweet taste receptor has been reported in numerous extragustatory tissues, including the gut, pancreas, bladder, brain and, more recently, bone and adipose tissues. In the gut, this receptor has been suggested to be involved in luminal glucose sensing, the release of some satiety hormones, the expression of glucose transporters, and the maintenance of glucose homeostasis. More recently, the sweet taste receptor was proposed to regulate adipogenesis and bone biology.

Summary: The perception of sweet taste is mediated by the T1R2/T1R3 receptor, which is expressed in the oral cavity, wherein it provides input on the caloric and macronutrient contents of ingested food. This receptor recognizes all the chemically diverse compounds perceived as sweet by human beings, including natural sugars and sweeteners. Importantly, the expression of a functional sweet taste receptor has been reported in numerous extragustatory tissues, wherein it has been proposed to regulate metabolic processes. This newly recognized role of the sweet taste receptor makes this receptor a potential novel therapeutic target for the treatment of obesity and related metabolic dysfunctions, such as diabetes and hyperlipidemia.

Box 1

no caption available

FIGURE 1

Schematic model of the sweet taste receptor. The sweet taste receptor is composed of two subunits, T1R2 and T1R3. The two subunits belong to the class C GPCRs. T1R2 and T1R3 possess a large aminoterminal domain (ATD) that includes a Venus flytrap domain (VFT) connected to a helical transmembrane domain (TMD) (characteristic of GPCRs) by a short cysteine-rich domain (CRD). The VFT is composed of two lobes separated by a large cleft, in which most sweeteners bind. GPCRs, G protein-coupled receptors.

FIGURE 2

Signaling through T1R2/T1R3 in type II cells of taste buds, in the gut and in the β cells of the pancreas. In the taste buds, activated T1R2/T1R3 interacts with heterotrimeric G proteins comprising α-gustducin, Gβ3, and Gγ13. After the dissociation of the G protein subunits, the Gβγ subunit interacts with phospholipase C-β2 (PLC-β2), which in turn cleaves phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-triphosphate (IP₃), producing diacylglycerol (DAG). IP₃ stimulates Ca²⁺ release from the endoplasmic reticulum (ER) via type III IP₃ receptor activation (IP3-R). The elevated intracellular Ca²⁺ activates the TRPM5 channel, leading to membrane depolarization, which enables the ATP channel Pannexin-1 (PX1) to open and release ATP, which stimulates efferent nerve fibers. In the gut, the signal transduction pathway is similar to that described in taste buds. The glucose (Glc) stimulation of the T1R2/T1R3 receptor triggers the secretion of two incretins, GLP-1 and GIP, and increases the expression of sodium-glucose cotransporter-1 (SGLT-1) to the plasma membrane. In the β cells of the pancreas, Glc is transported by glucose transporter-2 (GLUT-2). Glycolysis leads to an ATP increase, leading to K_ATP channel closure, which causes depolarization. This depolarization, in turn, activates the voltage-dependent calcium channel (VDCC), leading to the accumulation of Ca²⁺ in the cytoplasm and to insulin secretion. The T1R2/T1R3 receptor has been proposed to be implicated in the regulation of insulin secretion. ATP, adenosine triphosphate; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; TRPM5, transient receptor potential cation channel subfamily M member 5.

FIGURE 3

Oral and extraoral tissues where T1R2/T1R3 or α-gustducin have been described as being expressed. The reference numbers are indicated in brackets.