Distinct Contributions of T1R2 and T1R3 Taste Receptor Subunits to the Detection of Sweet Stimuli

Abstract

Animals utilize hundreds of distinct G protein-coupled receptor (GPCR)-type chemosensory receptors to detect a diverse array of chemical signals in their environment, including odors, pheromones, and tastants. However, the molecular mechanisms by which these receptors selectively interact with their cognate ligands remain poorly understood. There is growing evidence that many chemosensory receptors exist in multimeric complexes, though little is known about the relative contributions of individual subunits to receptor functions. Here, we report that each of the two subunits in the heteromeric T1R2:T1R3 sweet taste receptor binds sweet stimuli though with distinct affinities and conformational changes. Furthermore, ligand affinities for T1R3 are drastically reduced by the introduction of a single amino acid change associated with decreased sweet taste sensitivity in behaving mice. Thus, individual T1R subunits increase the receptive range of the sweet taste receptor, offering a functional mechanism for phenotypic variations in sweet taste.

Artificial Sweeteners Stimulate Adipogenesis and Suppress Lipolysis Independently of Sweet Taste Receptors

“…Some groups have hypothesized that T1R2/T1R3 does not function as an obligate heterodimer (42,43), but rather each component functions independently as a homodimer, consistent with the N-terminal domains of both T1R2 and T1R3 containing ligand-binding sites and changing conformation in response to artificial sweeteners (13). The homodimerization model has found support from Shibata and co-workers (55), who have investigated sweet taste receptor activity in cultured 3T3-L1 and adipose tissue stromal cells.…”

“…Additionally, binding of artificial sweeteners to the N-terminal domain of T1R2 or T1R3 in the absence of its dimerization partner suggests that these receptors may be capable of functioning independently (13,25,26). Although the input of T1R2/T1R3 may be important in the tongue and certain metabolic tissues, these studies indicate that there may be additional receptors sensitive to carbohydrates and sweeteners.…”

“…Sugars and artificial sweeteners such as saccharin (Sacc) and acesulfame potassium (AceK) bind primarily to T1R2 (12), although direct binding to T1R3 has been described (13). Originally characterized in the tongue as a mediator of saccharin preference, these receptors have subsequently been described in the brain, bladder, pancreas, and gut (14 -17) with metabolic roles defined in the latter two tissues.…”

Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects

“…For example, sucrose binds with a different affinity from sucralose (33), whereas absence of T1R3 receptors in knockout mice completely abolishes any taste preference for sucralose but merely diminishes the preference for sucrose (9). Moreover, functional brain imaging in humans indicates differences in central activation between sucrose and identically sweet sucralose solutions (13).…”

Molecular mechanism for the umami taste synergism

“…Using human-rat chimeric receptors, we demonstrated the T1R2 VFT domain of the human sweet receptor interacts with 2 structurally related synthetic sweeteners aspartame and neotame, while the transmembrane domain (TMD) of human T1R3 interacts with another sweetener cyclamate and a human sweet-taste inhibitor lactisole (7). Works from several other laboratories indicated potential roles in ligand interaction for the T1R3 VFT domain (10,11) and Cys-rich region (12).…”