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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    • "While both T1R2 and T1R3 KO animals have significantly impaired sweet taste sensitivity, there has been some suggestion that T1R2 and T1R3 may be capable of functioning independently as homodimers [14], [15], [29]. Work from the Munger group has suggested that T1R3, in particular, may be the primary mediator of T1R2/T1R3 signaling [14], [30]. "
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    ABSTRACT: Functional expression of sweet taste receptors (T1R2 and T1R3) has been reported in numerous metabolic tissues, including the gut, pancreas, and, more recently, in adipose tissue. It has been suggested that sweet taste receptors in these non-gustatory tissues may play a role in systemic energy balance and metabolism. Smaller adipose depots have been reported in T1R3 knockout mice on a high carbohydrate diet, and sweet taste receptors have been reported to regulate adipogenesis in vitro. To assess the potential contribution of sweet taste receptors to adipose tissue biology, we investigated the adipose tissue phenotypes of T1R2 and T1R3 knockout mice. Here we provide data to demonstrate that when fed an obesogenic diet, both T1R2 and T1R3 knockout mice have reduced adiposity and smaller adipocytes. Although a mild glucose intolerance was observed with T1R3 deficiency, other metabolic variables analyzed were similar between genotypes. In addition, food intake, respiratory quotient, oxygen consumption, and physical activity were unchanged in T1R2 knockout mice. Although T1R2 deficiency did not affect adipocyte number in peripheral adipose depots, the number of bone marrow adipocytes is significantly reduced in these knockout animals. Finally, we present data demonstrating that T1R2 and T1R3 knockout mice have increased cortical bone mass and trabecular remodeling. This report identifies novel functions for sweet taste receptors in the regulation of adipose and bone biology, and suggests that in these contexts, T1R2 and T1R3 are either dependent on each other for activity or have common independent effects in vivo.
    PLoS ONE 01/2014; 9(1):e86454. DOI:10.1371/journal.pone.0086454 · 3.23 Impact Factor
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    • "Analyses of the Tas1r3 sequence variants across multiple inbred strains identified a missense polymorphism (I60T) in the extracellular N-terminus of the T1R3 protein as a candidate causative variant for ligand binding and phenotypical variation in sweet taste [94]. The effect of this polymorphism on T1R3 ligand binding was confirmed in vitro [113]. Tas1r3 polymorphisms affect behavioral and neural taste responses to many different sweeteners [114] [115], indicating that these sweeteners activate a taste receptor involving T1R3. "
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    ABSTRACT: Taste receptors function as one of the interfaces between internal and external milieus. Taste receptors for sweet and umami (T1R [taste receptor, type 1]), bitter (T2R [taste receptor, type 2]), and salty (ENaC [epithelial sodium channel]) have been discovered in the recent years, but transduction mechanisms of sour taste and ENaC-independent salt taste are still poorly understood. In addition to these five main taste qualities, the taste system detects such noncanonical "tastes" as water, fat, and complex carbohydrates, but their reception mechanisms require further research. Variations in taste receptor genes between and within vertebrate species contribute to individual and species differences in taste-related behaviors. These variations are shaped by evolutionary forces and reflect species adaptations to their chemical environments and feeding ecology. Principles of drug discovery can be applied to taste receptors as targets in order to develop novel taste compounds to satisfy demand in better artificial sweeteners, enhancers of sugar and sodium taste, and blockers of bitterness of food ingredients and oral medications.
    Current pharmaceutical design 07/2013; 20(16). DOI:10.2174/13816128113199990566 · 3.45 Impact Factor
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    • "During the last decade, the binding sites for several sweet compounds have been identified by means of biomolecular and biophysical experiments (Fig. 6b). Sucrose and glucose appear to bind to the VFT of both T1R2 and T1R3 subunits (Maitrepierre et al. 2012; Nie et al. 2005). Other substances, such as aspartame, interact with the VFT of only one, the human T1R2 subunit (Liu et al. 2011; Masuda et al. 2012; Xu et al. 2004). "
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    ABSTRACT: Sweet-tasting compounds are recognized by a heterodimeric receptor composed of the taste receptor, type 1, members 2 (T1R2) and 3 (T1R3) located in the mouth. This receptor is also expressed in the gut where it is involved in intestinal absorption, metabolic regulation, and glucose homeostasis. These metabolic functions make the sweet taste receptor a potential novel therapeutic target for the treatment of obesity and related metabolic dysfunctions such as diabetes. Existing sweet taste inhibitors or blockers that are still in development would constitute promising therapeutic agents. In this review, we will summarize the current knowledge of sweet taste inhibitors, including a sweet-taste-suppressing protein named gurmarin, which is only active on rodent sweet taste receptors but not on that of humans. In addition, their potential applications as therapeutic tools are discussed.
    Applied Microbiology and Biotechnology 09/2012; 96(3):619-30. DOI:10.1007/s00253-012-4387-3 · 3.34 Impact Factor
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