Article

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

Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Current Biology (Impact Factor: 9.57). 12/2005; 15(21):1948-52. DOI: 10.1016/j.cub.2005.09.037
Source: PubMed

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.

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Available from: Jeanette R Hobbs, Feb 25, 2014
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    • "The significantly higher carbohydrate intake observed among the Val/Val genotype carriers may be attributed to a corresponding increase in the average daily intake of cereals. One plausible explanation may be that genetically speaking, the Ile191Val polymorphism resides in the predicted first large extracellular domain of the TAS1R2 receptor, which hypothetically contains the ligand-binding site for carbohydrates and dipeptide sweeteners444546. Particularly, this functional domain also displays significant genetic polymorphism and haplotype diversity presumably associated with the evolutionary adaptation humans have made by natural sugar nutrients [23]. "
    [Show abstract] [Hide abstract] ABSTRACT: Some high-carbohydrate diets may lead to obesity and multiple metabolic disorders, including hypertriglyceridemia (HTG). This lipid abnormality is considered an important risk factor for cardiovascular disease and type 2 diabetes. The sweet taste receptor TAS1R2 polymorphism (Ile191Val) has been reported to be associated with carbohydrate intake. The aim of this study was to analyze the association of the TAS1R2 gene polymorphism with carbohydrate intake and HTG among the population ofWest Mexico. In a cross-sectional study, 441 unrelated subjects were analyzed for TAS1R2 genotypes (Ile/Ile, Ile/Val and Val/Val) by an allelic discrimination assay. Biochemical tests and a three-day food record were assessed. The Val/Val genotype carriers had a higher intake of total carbohydrates, fiber and servings of cereals and vegetables than the other genotype carriers. The Val/Val genotype conferred a higher risk for HTG than the Ile/Val and Ile/Ile genotypes (OR = 3.26, 95%CI 1.35–7.86, p = 0.006 and OR = 2.61, 95%CI 1.12–6.07, p = 0.02, respectively). Furthermore, the Val/Val genotype was associated with approximately 30% higher triglycerides compared with Ile/Val and Ile/Ile genotypes (b = 44.09, 95%CI 9.94–78.25, p = 0.01 and b = 45.7, 95%CI 10.85–80.54, p = 0.01, respectively). In conclusion, the Val/Val genotype of TAS1R2 was associated with a higher carbohydrate intake and HTG.
    Full-text · Article · Feb 2016 · Nutrients
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    • "Current working concept suggests, increase in secondary structure content for the extracellular domain upon ligand binding, similar to mGluR. However, circular dichroism studies by independent groups show, decrease in secondary structure content on ligand binding [26] [27] "
    [Show abstract] [Hide abstract] ABSTRACT: Validation of research methodology is critical in research design. Correlation between experimental observables must be established before undertaking extensive experiments or propose mechanisms. This article shows that, observables in the popular calcium flux strength assay used in the characterization of sweetener-sweet taste receptor (STR) interaction are uncorrelated. In pursuit to find potential sweeteners and enhancers, calcium flux generated via G-protein coupling for wildtype and mutant receptors expressed on cell surface is measured to identify and localize sweetener binding sites. Results are channeled for sweetener development with direct impact on public health. We show that flux strength is independent of EC50 and sweet potency. Sweet potency-EC50 relation is non-linear and anti-correlated. Single point mutants affecting receptor efficiency, without significant shift in EC50 have been published, indicating flux strength is independent of ligand binding. G-protein coupling step is likely observed in the assay. Thus, years have been spent generating uncorrelated data. Data from uncorrelated observables does not give meaningful results. Still, majority of research in the field, uses change in calcium flux strength to study the receptor. Methodology away from flux strength monitor is required for sweetener development, reestablish binding localization of sweeteners established by flux strength method. This article serves to remind researchers to validate methodology before plunging into long term projects. Ignoring validation test on methodology, have been a costly mistake in the field. Concepts discussed here is applicable, whenever observable in biological systems are many steps moved from the event of interest.
    Preview · Article · Nov 2015
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    • "These receptors have a transmembrane domain (TMD) and a large extracellular domain (ECD), which is composed of a large extracellular venus flytrap domain (VFD) and a short cysteine-rich domain (CRD) [12,13]. Several reports show that the ECD is responsible for agonist recognition14151617 . Aspartame and acesulfame K are recognized by the ECD of human T1R2 (hT1R2). "
    [Show abstract] [Hide abstract] ABSTRACT: Although the five basic taste qualities-sweet, sour, bitter, salty and umami-can be recognized by the respective gustatory system, interactions between these taste qualities are often experienced when food is consumed. Specifically, the umami taste has been investigated in terms of whether it enhances or reduces the other taste modalities. These studies, however, are based on individual perception and not on a molecular level. In this study we investigated umami-sweet taste interactions using umami compounds including monosodium glutamate (MSG), 5'-mononucleotides and glutamyl-dipeptides, glutamate-glutamate (Glu-Glu) and glutamate-aspartic acid (Glu-Asp), in human sweet taste receptor hT1R2/hT1R3-expressing cells. The sensitivity of sucrose to hT1R2/hT1R3 was significantly attenuated by MSG and umami active peptides but not by umami active nucleotides. Inhibition of sweet receptor activation by MSG and glutamyl peptides is obvious when sweet receptors are activated by sweeteners that target the extracellular domain (ECD) of T1R2, such as sucrose and acesulfame K, but not by cyclamate, which interact with the T1R3 transmembrane domain (TMD). Application of umami compounds with lactisole, inhibitory drugs that target T1R3, exerted a more severe inhibitory effect. The inhibition was also observed with F778A sweet receptor mutant, which have the defect in function of T1R3 TMD. These results suggest that umami peptides affect sweet taste receptors and this interaction prevents sweet receptor agonists from binding to the T1R2 ECD in an allosteric manner, not to the T1R3. This is the first report to define the interaction between umami and sweet taste receptors.
    Full-text · Article · Apr 2015 · PLoS ONE
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