{"gene":"TAS1R3","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2001,"finding":"TAS1R3 (T1R3) was identified as a G protein-coupled receptor encoded by the Sac locus, the major determinant of sweet taste sensitivity differences between mouse strains. Sequence comparison across taster and non-taster strains identified a polymorphism (Ile60Thr) predicted to introduce an extra N-terminal glycosylation site in non-tasters that would interfere with receptor dimerization.","method":"Positional cloning, sequence analysis, structural modeling","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — positional cloning plus sequence polymorphism analysis in multiple strains; dimerization interference is structural prediction only, not experimentally confirmed in this paper","pmids":["11326277"],"is_preprint":false},{"year":2003,"finding":"Mice lacking T1R3 showed no preference for artificial sweeteners and had diminished (but not abolished) behavioral and nerve responses to sugars and umami compounds, demonstrating T1R3 is required for artificial sweetener detection but that T1R3-independent sweet/umami pathways also exist.","method":"T1R3 knockout mice; behavioral preference tests; chorda tympani nerve recordings","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout phenotype with both behavioral and electrophysiological readouts, widely replicated across subsequent studies","pmids":["12869700"],"is_preprint":false},{"year":2003,"finding":"T1R3 is essential for cellular recognition of the disaccharide trehalose, demonstrated using a heterologous expression system where T1R3 alone conferred responsiveness to trehalose.","method":"Heterologous expression assay in cell line","journal":"In vitro cellular & developmental biology. Animal","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single heterologous expression method, no mutagenesis confirmation","pmids":["12892531"],"is_preprint":false},{"year":2004,"finding":"The cysteine-rich region (CRD) of human T1R3 determines species-specific sensitivity to sweet proteins brazzein, monellin, and thaumatin. Site-directed mutagenesis within the CRD of T1R3 affected receptor activity toward these proteins and overall receptor efficacy, identifying the CRD as an important ligand-interaction domain.","method":"Chimeric receptor expression, site-directed mutagenesis, heterologous expression assay in HEK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional validation in heterologous expression, multiple mutants tested, single lab","pmids":["15299024"],"is_preprint":false},{"year":2005,"finding":"The transmembrane domain of human T1R3 is required for sweet receptor responsiveness to cyclamate. Alanine-scanning mutagenesis of the predicted transmembrane binding pocket identified six residues critical for cyclamate response; molecular modeling docked cyclamate within this pocket, and predicted overlap between cyclamate (agonist) and lactisole (inverse agonist) binding sites.","method":"Mixed-species chimeric receptors, directed mutagenesis, alanine scanning, molecular modeling, heterologous expression assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic alanine-scanning mutagenesis combined with chimera analysis and molecular docking in a single rigorous study","pmids":["16076846"],"is_preprint":false},{"year":2005,"finding":"Each subunit (T1R2 and T1R3) of the heteromeric sweet receptor independently binds sweet stimuli with distinct affinities and conformational changes. A single amino acid change in T1R3 associated with decreased sweet sensitivity in mice drastically reduced ligand affinities for T1R3, demonstrating that T1R3 expands the receptive range of the sweet receptor.","method":"Ligand binding assays with expressed N-terminal domain proteins, site-directed mutagenesis","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding assays with purified domains plus mutagenesis confirming functional role of specific residue, single lab","pmids":["16271873"],"is_preprint":false},{"year":2006,"finding":"The ligand-binding N-terminal domain (NTD) of mouse T1R3 was expressed as fusion proteins in E. coli, purified, and shown to be properly folded and capable of binding ligands by spectroscopic analysis, establishing that the T1R3 NTD is a functional autonomous ligand-binding module.","method":"Heterologous protein expression (E. coli), column chromatography purification, circular dichroism spectroscopy, ligand binding assays","journal":"Chemical senses","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution of domain with binding confirmation, single lab, limited ligand characterization","pmids":["16621970"],"is_preprint":false},{"year":2007,"finding":"T1R3 and the taste G protein gustducin, expressed in intestinal enteroendocrine cells, underlie luminal sugar sensing and regulation of SGLT1 mRNA and protein expression. Knockout mice lacking T1R3 or alpha-gustducin failed to upregulate SGLT1 in response to dietary sugars or artificial sweeteners, and artificial sweeteners acting on enteroendocrine GLUTag cells stimulated gut hormone secretion implicated in SGLT1 upregulation.","method":"T1R3 and alpha-gustducin knockout mice; SGLT1 mRNA/protein measurement; GLUTag cell stimulation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with molecular readout replicated in two KO lines plus in vitro enteroendocrine cell model","pmids":["17724332"],"is_preprint":false},{"year":2007,"finding":"C/EBPbeta activates the human TAS1R3 promoter, as demonstrated by luciferase reporter assay and EMSA in bile duct carcinoma cells (HuCCT1). The proximal 226-bp upstream of ATG contains the core promoter activity.","method":"5'-RACE, luciferase reporter assay, EMSA","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional promoter assay plus EMSA, single lab, single cell line","pmids":["17928076"],"is_preprint":false},{"year":2008,"finding":"T1R3 functions as a gustatory calcium-magnesium receptor. Genome scan linked calcium/magnesium preference to the Tas1r3 locus; Tas1r3 knockout mice preferred calcium solutions avoided by wild-type mice; oral calcium elicited reduced chorda tympani nerve activity in Tas1r3 knockout mice. A V689A substitution unique to the PWK strain was associated with strong calcium/magnesium preference.","method":"Genome scan, congenic and knockout mice, chorda tympani nerve electrophysiology, two-bottle preference tests, sequence analysis","journal":"Physiological genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic approaches (genome scan, congenic, knockout) with both behavioral and electrophysiological readouts","pmids":["18593862"],"is_preprint":false},{"year":2009,"finding":"Two promoter SNPs at -1572 (rs307355) and -1266 (rs35744813) upstream of TAS1R3 reduce promoter activity as shown by luciferase reporter assay; the T allele of each SNP results in lower activity. A distal silencing element in the TAS1R3 promoter was also characterized, demonstrating transcriptional regulation of TAS1R3 expression.","method":"Luciferase reporter assay, human genetic association, population survey","journal":"Current biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay corroborating genetic association; two independent SNPs tested with same directional effect","pmids":["19559618"],"is_preprint":false},{"year":2009,"finding":"Direct binding of sweet agonists and antagonists to the full heterodimeric T1R2/T1R3 receptor in native membrane preparations was detected by saturation transfer difference (STD) NMR, allowing distinction between mutations affecting ligand-binding sites versus downstream signal transduction.","method":"Saturation transfer difference NMR spectroscopy on membrane preparations from HEK293 cells expressing sweet receptor","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct binding NMR on native membranes, single lab, no mutagenesis validation in same paper","pmids":["19664591"],"is_preprint":false},{"year":2009,"finding":"Phenoxyauxin herbicides and lipid-lowering fibrates inhibit human T1R3 but not rodent T1R3, identifying these compounds as species-selective T1R3 inhibitors.","method":"Heterologous expression assay comparing human vs. rodent T1R3","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional receptor assay with species comparison, single lab","pmids":["19817384"],"is_preprint":false},{"year":2010,"finding":"Key amino acid residues in brazzein (sites 1–3) and in the T1R2 Venus flytrap module are required for brazzein activation of the T1R2/T1R3 sweet receptor. Mutagenesis of receptor residue hT1R2:R217A selectively reduced brazzein activity and increased cooperativity for multiple ligands binding both subunits, implicating this site in subunit-subunit interaction rather than direct brazzein binding. Results support a multi-point interaction between brazzein and the sweet receptor not fitting the wedge model.","method":"Site-directed mutagenesis of brazzein and receptor subunits; HEK293 cell expression assay; human taste panel","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis of both ligand and receptor with functional in vitro assay plus human taste panel, single lab but multiple orthogonal methods","pmids":["20302879"],"is_preprint":false},{"year":2011,"finding":"T1R3 knockout mice lacking T1R3 or alpha-gustducin failed to upregulate intestinal SGLT1 in response to sugars. T1R3-expressing taste cells in the tongue were shown by RT-PCR, qPCR, in situ hybridization, and immunohistochemistry to co-express GLUT4, SGLT1, and SUR1 (a KATP channel component), suggesting T1R3+ cells are equipped for metabolic glucose sensing independent of T1R2+T1R3.","method":"RT-PCR, quantitative PCR, in situ hybridization, immunohistochemistry, electrophysiological recording of KATP currents","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular methods plus electrophysiology, single lab","pmids":["21383163"],"is_preprint":false},{"year":2011,"finding":"Human TAS1R3 polymorphisms F749S and R757C in the transmembrane domain severely impair in vitro T1R1/T1R3 response to MSG, as demonstrated by functional expression. A molecular model of the ligand-binding region provides a mechanistic explanation consistent with the functional data.","method":"Functional expression of polymorphic receptors in heterologous cells, molecular modeling","journal":"Chemical senses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional expression of natural variants with phenotypic confirmation, corroborated by molecular model","pmids":["21422378"],"is_preprint":false},{"year":2012,"finding":"T1R1/T1R3 functions as a direct cell-surface sensor of amino acid availability that regulates mTORC1 activity. Knockdown of T1R1/T1R3 reduces amino acid-stimulated mTORC1 signaling, alters mTORC1 localization, downregulates pathway inhibitors, upregulates amino acid transporters, blocks translation initiation, and induces autophagy in mammalian cells.","method":"siRNA knockdown; mTORC1 signaling assays (phosphorylation readouts); autophagy assays; subcellular localization imaging","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal cellular assays with genetic knockdown, published in high-impact journal, subsequently replicated by multiple labs","pmids":["22959271"],"is_preprint":false},{"year":2012,"finding":"T1R3 homodimer functions as a glucose-sensing receptor in pancreatic β-cells. Sucralose (T1R3 agonist) increased intracellular ATP even in the absence of glucose, augmented mitochondrial metabolism, and shRNA knockdown of T1R3 attenuated glucose-induced ATP elevation and insulin secretion.","method":"Luciferase-based ATP biosensor in MIN6 cells, shRNA knockdown of T1R3, pharmacological agonism with sucralose and 3-O-methylglucose","journal":"Endocrine journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell ATP imaging plus knockdown with insulin secretion readout, single lab, two orthogonal methods","pmids":["24200979"],"is_preprint":false},{"year":2012,"finding":"T1R2 and T1R3 are expressed in human and rat bladder urothelium. Saccharin augmented bladder smooth muscle contraction induced by electrical field stimulation only when urothelium was present; zinc (a T1R3 inhibitor) blocked this effect, indicating T1R3-dependent urothelial signaling mediates sweetener-augmented bladder contraction.","method":"Immunohistochemistry, immunoblotting, organ bath contractility assay with pharmacological inhibition","journal":"The Journal of urology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with urothelium-dependent functional assay, single lab","pmids":["22019168"],"is_preprint":false},{"year":2012,"finding":"Human T1R3 (hTAS1R3) expressed in HEK293 cells is activated by calcium, and this response is attenuated by lactisole (a T1R3 inhibitor). In trained human volunteers, lactisole reduced the perceived calcium intensity of calcium lactate, establishing T1R3 as a human calcium taste receptor.","method":"Heterologous expression (HEK293 transfection), pharmacological inhibition with lactisole, human psychophysical taste testing","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro receptor assay combined with human taste psychophysics with pharmacological blockade","pmids":["22773945"],"is_preprint":false},{"year":2012,"finding":"Human T1R3 surface membrane trafficking requires co-expression with human T1R2; human T1R3 alone is not trafficked to the membrane. The Venus flytrap module and cysteine-rich domain of human T1R3 contain regions that inhibit its membrane trafficking and coordinate its regulation. This is distinct from mouse T1r3, which reaches the membrane without T1r2.","method":"Tagged receptor expression in HEK293 cells, domain-swap chimeras, truncation mutants, cell surface localization assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic chimera/truncation analysis with direct membrane localization readout, single lab","pmids":["25029362"],"is_preprint":false},{"year":2012,"finding":"The N-terminal domain (NTD) of human T1R3 was refolded from E. coli inclusion bodies, shown to behave as a dimer by size-exclusion chromatography, and demonstrated to bind sucralose with millimolar affinity by tryptophan fluorescence quenching and microcalorimetry.","method":"Recombinant protein expression in E. coli, refolding, size-exclusion chromatography, circular dichroism, tryptophan fluorescence quenching, isothermal titration calorimetry","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with biophysical binding measurements, single lab, no functional signaling validation","pmids":["22450161"],"is_preprint":false},{"year":2012,"finding":"T1R1-T1R3 expressed in intestinal enteroendocrine cells mediates CCK secretion in response to L-amino acids (Phe, Leu, Glu) but not Trp. siRNA knockdown of T1R1 in STC-1 cells reduced Phe-, Leu-, and Glu-stimulated CCK release; the T1R3 inhibitor gurmarin also blocked these responses, while the Ca2+-sensing receptor antagonist blocked only Trp-stimulated CCK secretion.","method":"siRNA knockdown of T1R1, pharmacological inhibition with gurmarin and NPS2143, CCK secretion assay in STC-1 cells and intestinal tissue explants","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic (siRNA) and pharmacological inhibition with specific physiological readout, tested in both cell line and ex vivo tissue","pmids":["23203156"],"is_preprint":false},{"year":2013,"finding":"T1R1/T1R3 exhibits species-dependent ligand specificity determined by 12 key residues in the Venus flytrap domain of T1R1. Residues critical for human-type acidic amino acid recognition are at the orthosteric binding site, while residues mediating mouse-type broad responses are outside both orthosteric and IMP allosteric sites, demonstrating two distinct determinants of ligand specificity.","method":"Chimeric human-mouse receptor analysis, site-directed mutagenesis, heterologous expression functional assays, molecular modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic chimera and mutagenesis study with functional assays identifying two distinct molecular mechanisms, single lab","pmids":["24214976"],"is_preprint":false},{"year":2014,"finding":"L-theanine activates the T1R1+T1R3 umami receptor and shows synergy with IMP. Site-directed mutagenesis demonstrated that L-theanine binds to the L-amino acid binding site in the Venus flytrap domain of T1R1.","method":"Heterologous expression functional assay, site-directed mutagenesis, IMP synergy assay","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with functional assay confirming binding site, single lab","pmids":["24633359"],"is_preprint":false},{"year":2014,"finding":"T1R1/T1R3 activation by luminal MSG or L-cysteine initiates the peristaltic reflex (ascending contraction, descending relaxation) and CGRP release in rat colon flat-sheet preparations. IMP augmented these effects. In T1R1 knockout mice, mucosal stroking but not MSG elicited a peristaltic reflex. MSG also enhanced fecal pellet propulsion velocity in guinea pig distal colon.","method":"T1R1 knockout mice; three-chamber flat-sheet colon preparation; electrophysiology; CGRP release assay; video recording of pellet propulsion","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout plus pharmacological and ex vivo functional readouts in multiple species/preparations","pmids":["25324508"],"is_preprint":false},{"year":2014,"finding":"Mouse neutrophils express functional T1R1/T1R3: stimulation with L-alanine or L-serine (umami receptor ligands) elicited ERK/p38 MAPK phosphorylation and chemotactic migration, and reduced LPS-induced cytokine production (TNF-α) through inhibition of NF-κB and STAT3 phosphorylation.","method":"RNA sequencing, qRT-PCR, signaling assays (ERK/p38 phosphorylation), chemotaxis assay, cytokine measurement, NF-κB/STAT3 activity assay","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional assays in primary neutrophils, single lab, no receptor knockdown control shown","pmids":["25301019"],"is_preprint":false},{"year":2015,"finding":"Lactisole inhibits the mouse glucose-sensing T1R3 receptor in MIN6 pancreatic β-cells. Lactisole attenuated sweetener-induced Ca2+ elevation and insulin secretion, and inhibited glucose-induced elevations of NADH, ATP, and insulin secretion. In HEK293 cells stably expressing mouse T1R3, lactisole attenuated sucralose-induced Ca2+ elevation but not cAMP elevation.","method":"Pharmacological inhibition assay in MIN6 cells, stably transfected HEK293-T1R3 cells, intracellular Ca2+/cAMP/NADH/ATP measurements, insulin secretion assay in mouse islets","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays plus ex vivo islet experiments, single lab","pmids":["25994004"],"is_preprint":false},{"year":2015,"finding":"Muscle regulatory factors MyoD and Myogenin bind the evolutionarily conserved T1R3 promoter and regulate T1R3 expression; T1R3 expression increases with C2C12 myoblast differentiation. A repressive element upstream of the human T1R3 promoter was also identified.","method":"Comparative genomics, luciferase reporter assay, identification of binding sites for MyoD/Myogenin, qPCR of T1R3 expression during differentiation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional promoter assay with transcription factor identification, single lab","pmids":["26545778"],"is_preprint":false},{"year":2015,"finding":"Tas1r3 knockout mice showed reduced insulin sensitivity and impaired glucose tolerance following intraperitoneal or intragastric glucose administration, with impairment worsening with age after IP but not IG administration, indicating extraoral T1R3 (likely pancreatic/brain) has a role in glucose homeostasis independent of incretin effects (incretin responses were similar between KO and WT).","method":"Tas1r3 knockout mice; glucose and insulin tolerance tests; behavioral sucrose preference tests; incretin measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with multiple metabolic assays and control experiments ruling out incretin mechanism, single lab","pmids":["26107521"],"is_preprint":false},{"year":2016,"finding":"In C2C12 myotubes, methionine activates mTORC1 through the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 signaling axis. T1R1 and T1R3 are expressed in these cells, and methionine was the most potent amino acid among those tested in activating this pathway.","method":"siRNA knockdown of T1R1/T1R3, intracellular Ca2+ measurement, ERK1/2 phosphorylation assay, mTORC1 activation assay, protein synthesis measurement","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with multiple signaling readouts, single lab","pmids":["27727170"],"is_preprint":false},{"year":2017,"finding":"T1R3 is expressed in the pulmonary vasculature. Sucralose (T1R3 agonist) attenuated LPS- and thrombin-induced endothelial barrier dysfunction and bacteria-induced lung edema in vivo. Protective effects were blocked by T1R3 siRNA or G-protein siRNA. Sucralose reduced LPS-induced Src, PAK, MLC2, HSP27, and p110αPI3K phosphorylation/expression.","method":"T1R3 siRNA knockdown, endothelial barrier permeability assay, in vivo lung edema model, signaling assays (Src/PAK/MLC2/HSP27/PI3K)","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with both in vitro and in vivo functional readouts plus downstream signaling characterization, single lab","pmids":["28971978"],"is_preprint":false},{"year":2017,"finding":"T1R1/T1R3 modulates the mTOR pathway in mouse mammary gland in vivo to regulate milk protein (β-casein) synthesis. T1R1 knockout reduced total milk yield and β-casein synthesis, decreased phosphorylation of 4EBP1 and S6K, and increased AA transporter (SLC3A2, SLC7A5, SLC1A5) expression.","method":"T1R1 knockout mice (mammary gland), weigh-suckle-weigh milk yield, qPCR, western blot of mTOR pathway","journal":"Molecular nutrition & food research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with multiple molecular and physiological readouts, single lab","pmids":["28497545"],"is_preprint":false},{"year":2017,"finding":"T1R3 homomeric sweet receptor negatively regulates adipogenesis through a Gαs-mediated but cAMP-independent mechanism. Sucralose/saccharin-induced T1R3 activation caused microtubule disassembly (blocked by dominant-negative Gαs), activated RhoA/ROCK through GEF-H1, and dominant-negative RhoA blocked sweetener-induced Akt dephosphorylation and suppression of PPARγ/C/EBPα.","method":"Dominant-negative/constitutively-active Gαs overexpression, RhoA dominant-negative mutants, GEF-H1 knockdown, microtubule staining, Akt/PPARγ/C/EBPα signaling assays in 3T3-L1 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic interventions (dominant negatives, knockdowns) with signaling readouts in single cell model, single lab","pmids":["28472098"],"is_preprint":false},{"year":2018,"finding":"Methional, a flavor compound, acts as a positive allosteric modulator (PAM) of human T1R1/T1R3 and a negative allosteric modulator (NAM) of mouse T1R1/T1R3. Interspecies chimeric receptor analysis demonstrated methional interacts with the transmembrane domain of T1R1 (not the extracellular domain). Site-directed mutagenesis and molecular modeling identified two distinct binding sites in the T1R1 transmembrane domain and showed that residues at the bottom of the allosteric pocket determine PAM vs. NAM switching.","method":"Interspecies chimeric receptors, site-directed mutagenesis, heterologous expression functional assay, molecular modeling","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — chimera analysis, mutagenesis, and molecular modeling in single study identifying mechanism of PAM/NAM switching, multiple orthogonal methods","pmids":["30087430"],"is_preprint":false},{"year":2018,"finding":"Cyclamate and acesulfame K modulate proton secretion in human gastric parietal cells (HGT-1) through T1R3. T1R3 siRNA knockdown and co-treatment with lactisole (T1R3 inhibitor) reduced the effect of both sweeteners and d-threonine on proton release, establishing T1R3 as a key mediator of gastric acid secretion responses to these compounds.","method":"TAS1R3 siRNA knockdown, pharmacological inhibition with lactisole, intracellular pH assay, RT-qPCR, immunocytochemistry","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus pharmacological inhibition converging on same phenotype, single lab","pmids":["29665689"],"is_preprint":false},{"year":2018,"finding":"Val and Met activate mTOR signaling in bovine mammary epithelial cells through TAS1R1/TAS1R3, elevating intracellular calcium. TAS1R1 siRNA knockdown reduced Val- and Met-induced intracellular Ca2+ elevation, decreased mTOR/S6K1/4EBP1 phosphorylation, and reduced β-casein (CSN2) mRNA abundance.","method":"siRNA knockdown of TAS1R1 in primary bovine mammary epithelial cells and Mac-T cells, intracellular Ca2+ measurement, western blot of mTOR pathway, qPCR","journal":"Journal of dairy science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with Ca2+ and mTOR pathway readouts in primary cells, single lab","pmids":["30268610"],"is_preprint":false},{"year":2020,"finding":"Artificial sweeteners sucralose and aspartame increased intestinal epithelial permeability and downregulated claudin-3 at the cell surface; T1R3 knockdown attenuated these effects. Aspartame induced ROS production to cause permeability and claudin-3 internalization; claudin-3 overexpression rescued sweetener-induced permeability, placing T1R3 upstream of oxidative stress and tight junction disruption.","method":"T1R3 siRNA knockdown in Caco-2 cells, epithelial permeability assay, claudin-3 surface localization, ROS measurement, claudin-3 overexpression rescue","journal":"Nutrients","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown and overexpression rescue with multiple cellular readouts, single lab","pmids":["32580504"],"is_preprint":false},{"year":2020,"finding":"TAS1R3 is required for normal tuft cell homeostasis in the distal small intestine. Tas1r3-deficient mice had a severe decrease in distal small intestinal tuft cells at homeostasis, and both BALB/c mice (bearing inactive TAS1R3) and Tas1r3-deficient C57BL6/J mice had severely impaired type 2 immune responses to the protozoa Tritrichomonas muris and succinate in the ileum.","method":"Tas1r3 knockout mice, tuft cell counting, parasite infection model, immune response measurement","journal":"ImmunoHorizons","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with cellular and immune phenotype, corroborated in two genetically distinct mouse models","pmids":["31980480"],"is_preprint":false},{"year":2018,"finding":"T1R3 is expressed in primary osteoclasts (confirmed by expression correlation with differentiation status) and its loss in Tas1r3 mutant mice is associated with >60% reduction in the bone resorption marker collagen type I C-telopeptide, while bone formation marker PINP is unchanged, indicating TAS1R3 influences bone remodeling primarily through osteoclast function.","method":"Tas1r3 mutant mice, serum bone marker assays (PINP, CTX-I), primary osteoclast culture with qPCR","journal":"Journal of physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo knockout phenotype with systemic marker readout, mechanistic pathway only partially defined, single lab","pmids":["29019082"],"is_preprint":false},{"year":2024,"finding":"Steviol glycosides bind to four distinct sites on the T1R2/T1R3 heterodimer: VFD2, VFD3, TMD2, and TMD3. The C20 carboxy terminus of the Gα protein binds the intracellular region of either TMD2 or TMD3, shifting the receptor to a high-affinity state for steviol glycosides. Lactisole (negative allosteric modulator) binding sites overlap with tested ligand sites.","method":"Radioligand binding experiments, computational docking to homology model, Gα protein binding assay","journal":"Communications chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — binding experiments plus computational docking, Gα interaction identified but not validated by mutagenesis, single lab","pmids":["39424933"],"is_preprint":false},{"year":2015,"finding":"Amino acids differentially regulate ERK1/2 and mTORC1 through T1R1/T1R3 in MIN6 pancreatic β-cells via distinct signaling pathways. Ca2+ entry is required for ERK1/2 but not mTORC1 activation; Gq (inhibited by UBO-QIC) is required for ERK1/2 but not mTORC1; pertussis toxin (Gi inhibitor) blocked neither pathway; amino acids did not affect cAMP, excluding Gs.","method":"Pharmacological inhibition of Gi (pertussis toxin), Gq (UBO-QIC), Gs (cAMP measurement), Ca2+ chelation; ERK1/2 and mTORC1 phosphorylation assays in MIN6 cells","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic pharmacological dissection of G-protein pathway with multiple readouts, single lab","pmids":["26168033"],"is_preprint":false},{"year":2018,"finding":"Activation of retinal microvascular endothelial T1R3 (but not T1R2) by sucralose attenuated VEGF-induced cell proliferation, migration, adhesion, tube formation, and Akt phosphorylation. T1R3 siRNA knockdown abolished these protective effects.","method":"T1R3 siRNA knockdown in RMVEC cells, proliferation/migration/adhesion/tube formation assays, Akt phosphorylation western blot","journal":"Graefe's archive for clinical and experimental ophthalmology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with multiple functional vasculogenic readouts plus signaling, single lab","pmids":["30353220"],"is_preprint":false}],"current_model":"TAS1R3 (T1R3) is a class C GPCR subunit that obligatorily heterodimerizes with T1R2 (sweet receptor) or T1R1 (umami receptor), contributing distinct ligand-binding sites: the cysteine-rich domain binds sweet proteins, the transmembrane domain binds cyclamate and serves as an allosteric modulation site (including for lactisole inhibition), and the N-terminal Venus flytrap domain can independently bind ligands; beyond taste cells, extraoral T1R3 homodimers or T1R1/T1R3 heterodimers function as nutrient/amino acid sensors that couple through Gq/Ca2+/ERK and mTORC1 pathways to regulate SGLT1 expression, insulin secretion, CCK secretion, peristalsis, autophagy, milk protein synthesis, tuft cell homeostasis, bone resorption, and endothelial barrier function."},"narrative":{"mechanistic_narrative":"TAS1R3 (T1R3) is a class C G protein-coupled receptor subunit that functions as the shared partner of the heteromeric sweet (T1R2/T1R3) and umami (T1R1/T1R3) taste receptors, and as the major genetic determinant of mouse sweet-taste sensitivity encoded by the Sac locus [PMID:11326277, PMID:12869700]. Genetic ablation of T1R3 abolishes preference for artificial sweeteners and diminishes responses to sugars and umami compounds, while leaving residual T1R3-independent sweet/umami signaling intact [PMID:12869700]. Within these heterodimers, T1R3 contributes distinct, spatially separable ligand-interaction surfaces: its cysteine-rich domain governs species-specific recognition of sweet proteins such as brazzein, monellin, and thaumatin [PMID:15299024]; its transmembrane domain houses the cyclamate agonist pocket that overlaps the lactisole inhibitor site [PMID:16076846]; and its N-terminal Venus flytrap domain is an autonomous, dimerizing module that independently binds sweet ligands with distinct affinity, thereby expanding the receptor's receptive range [PMID:16271873, PMID:16621970, PMID:22450161]. T1R3 also serves directly as a gustatory calcium-magnesium receptor in both mouse and human [PMID:18593862, PMID:22773945]. Beyond taste cells, extraoral T1R1/T1R3 and T1R3 homodimers act as nutrient and amino-acid sensors that couple, via Gq/Ca2+/ERK signaling, to the mTORC1 pathway: T1R1/T1R3 regulates amino-acid-stimulated mTORC1 activity, translation, and autophagy [PMID:22959271, PMID:26168033], drives milk protein synthesis in mammary epithelium [PMID:28497545, PMID:30268610], and underlies enteroendocrine sugar sensing and SGLT1 upregulation [PMID:17724332]. T1R3-dependent signaling further mediates intestinal CCK secretion, colonic peristalsis, pancreatic insulin secretion and glucose homeostasis, gastric acid secretion, tuft cell homeostasis, osteoclast-driven bone resorption, and endothelial barrier integrity [PMID:23203156, PMID:25324508, PMID:24200979, PMID:26107521, PMID:29665689, PMID:31980480, PMID:29019082, PMID:28971978]. Human T1R3 surface trafficking is obligately dependent on co-expression with T1R2, distinguishing it from mouse T1r3 [PMID:25029362]. Its expression is transcriptionally controlled by C/EBPβ and the myogenic factors MyoD/Myogenin, and modulated by promoter polymorphisms [PMID:17928076, PMID:26545778, PMID:19559618].","teleology":[{"year":2001,"claim":"Established the molecular identity of the sweet-taste determinant by mapping the Sac locus to a GPCR gene, transforming a classical genetic trait into a defined receptor.","evidence":"Positional cloning and cross-strain sequence analysis identifying a dimerization-relevant polymorphism","pmids":["11326277"],"confidence":"Medium","gaps":["Dimerization interference was a structural prediction, not experimentally confirmed","Did not define ligand-binding mechanism or signaling partners"]},{"year":2003,"claim":"Demonstrated genetically that T1R3 is required for artificial sweetener detection and contributes to sugar/umami sensing, while revealing that parallel T1R3-independent pathways also exist.","evidence":"T1R3 knockout mice with behavioral preference tests and chorda tympani nerve recordings","pmids":["12869700"],"confidence":"High","gaps":["Did not identify the residual T1R3-independent sweet/umami pathway","Did not resolve which dimer partner mediates which modality"]},{"year":2004,"claim":"Localized species-specific sweet-protein recognition to a discrete T1R3 domain, beginning the dissection of T1R3's modular ligand-binding architecture.","evidence":"Chimeric receptors and CRD site-directed mutagenesis in HEK cells","pmids":["15299024"],"confidence":"High","gaps":["Did not establish whether CRD binds sweet proteins directly versus allosterically","No structural model of the protein-receptor interface"]},{"year":2005,"claim":"Assigned distinct ligand-binding roles to separate T1R3 domains, showing the transmembrane domain binds cyclamate (overlapping the lactisole site) and the N-terminal domain independently binds ligands to broaden the receptor's range.","evidence":"Alanine-scanning and chimera mutagenesis with molecular docking; N-terminal-domain binding assays plus mutagenesis","pmids":["16076846","16271873"],"confidence":"High","gaps":["Precise allosteric coupling between TMD and signal output unresolved","Conformational changes inferred indirectly"]},{"year":2006,"claim":"Confirmed the T1R3 N-terminal domain is an autonomous, properly folded ligand-binding module by reconstituting it in isolation.","evidence":"E. coli expression, purification, circular dichroism, and ligand binding of mouse T1R3 NTD","pmids":["16621970"],"confidence":"Medium","gaps":["Limited ligand panel tested","No coupling to downstream signaling demonstrated"]},{"year":2007,"claim":"Extended T1R3 function beyond the tongue, showing intestinal T1R3/gustducin sense luminal sugars and sweeteners to regulate SGLT1 expression and gut hormone secretion.","evidence":"T1R3 and alpha-gustducin knockout mice with SGLT1 readouts plus GLUTag enteroendocrine cell assays","pmids":["17724332"],"confidence":"High","gaps":["Intermediate signaling between receptor and SGLT1 transcription not fully mapped","Did not define the dimer composition of the enteroendocrine sensor"]},{"year":2008,"claim":"Identified T1R3 as a gustatory calcium-magnesium receptor, expanding its ligand repertoire beyond sweet/umami compounds.","evidence":"Genome scan, congenic and knockout mice, nerve electrophysiology, and behavioral preference tests","pmids":["18593862"],"confidence":"High","gaps":["Binding site for divalent cations on T1R3 not localized","Dimer requirement for calcium sensing unresolved"]},{"year":2009,"claim":"Resolved transcriptional and biophysical features of T1R3, mapping functional promoter SNPs/silencer elements and detecting direct agonist/antagonist binding to the native heterodimer.","evidence":"Luciferase reporter assays with human genetics; saturation transfer difference NMR on native membranes; species-selective inhibitor screening","pmids":["19559618","19664591","19817384"],"confidence":"Medium","gaps":["NMR lacked in-paper mutagenesis to assign binding sites","Functional consequence of promoter SNPs in vivo not established"]},{"year":2010,"claim":"Refined the brazzein-receptor interaction model, implicating a T1R2 residue in subunit-subunit cooperativity rather than direct binding and arguing against a simple wedge model.","evidence":"Mutagenesis of both ligand and receptor subunits with HEK293 assays and human taste panel","pmids":["20302879"],"confidence":"High","gaps":["Structural basis of multi-point interaction not solved","Allosteric cooperativity mechanism inferred functionally"]},{"year":2011,"claim":"Demonstrated that natural human transmembrane-domain polymorphisms impair umami (MSG) responses and that T1R3+ taste cells co-express metabolic glucose-sensing machinery.","evidence":"Functional expression of polymorphic receptors with modeling; multi-method expression profiling and KATP electrophysiology in taste cells","pmids":["21422378","21383163"],"confidence":"Medium","gaps":["Whether T1R3+ metabolic sensing is independent of T1R2/T1R3 not definitively shown","Polymorphism effects not validated in human psychophysics"]},{"year":2012,"claim":"Established T1R1/T1R3 as a cell-surface amino-acid sensor controlling mTORC1, autophagy, and translation, and defined extraoral roles in insulin secretion, CCK release, bladder contraction, calcium taste, and human T1R2-dependent trafficking.","evidence":"siRNA/shRNA knockdown with mTORC1, autophagy, ATP, insulin, and CCK readouts; HEK293 expression with human taste psychophysics; chimera/truncation trafficking analysis; in vitro NTD biophysics","pmids":["22959271","24200979","22019168","22773945","20220","23203156","22450161"],"confidence":"High","gaps":["Direct amino-acid binding to T1R1/T1R3 versus indirect sensing not fully resolved","Mechanism linking receptor to mTORC1 relocalization undefined"]},{"year":2013,"claim":"Mapped two distinct molecular determinants of species-dependent umami ligand specificity within the T1R1 Venus flytrap domain, one orthosteric and one outside known binding sites.","evidence":"Human-mouse chimeras, site-directed mutagenesis, functional assays, and molecular modeling","pmids":["24214976"],"confidence":"High","gaps":["Structural basis of the non-orthosteric determinant unknown","Contribution of T1R3 residues to specificity not addressed"]},{"year":2014,"claim":"Defined umami ligand binding (L-theanine) at the T1R1 Venus flytrap site and extended T1R1/T1R3 signaling to colonic peristalsis and neutrophil chemotaxis/immunomodulation.","evidence":"Mutagenesis with functional and IMP-synergy assays; T1R1 knockout colon preparations with electrophysiology and CGRP assays; neutrophil signaling/chemotaxis assays","pmids":["24633359","25324508","25301019"],"confidence":"High","gaps":["Neutrophil study lacked receptor knockdown control","Downstream coupling from receptor to peristaltic reflex incompletely mapped"]},{"year":2015,"claim":"Dissected the G-protein logic of extraoral T1R1/T1R3 signaling, showing Gq/Ca2+ drive ERK1/2 while mTORC1 activation is Gq- and Ca2+-independent, and defined transcriptional control by myogenic factors.","evidence":"Pharmacological G-protein dissection and phosphorylation assays in MIN6 cells; lactisole inhibition of glucose-sensing T1R3; promoter/transcription-factor reporter assays during myoblast differentiation","pmids":["26168033","25994004","26545778","26107521"],"confidence":"Medium","gaps":["The G-protein-independent route to mTORC1 not identified","Tissue specificity of transcriptional regulators not established in vivo"]},{"year":2017,"claim":"Identified divergent G-protein outputs of homomeric T1R3 (Gαs-mediated, cAMP-independent control of adipogenesis via RhoA/microtubules) and extended T1R3 to milk protein synthesis and endothelial barrier protection.","evidence":"Dominant-negative Gαs/RhoA and GEF-H1 knockdown in 3T3-L1 cells; T1R1 knockout mammary gland; T1R3/G-protein siRNA in pulmonary endothelium with in vivo edema models","pmids":["28472098","28497545","28971978"],"confidence":"Medium","gaps":["How a single receptor selects Gq versus Gαs outputs across tissues is unresolved","Adipogenesis mechanism shown in a single cell model"]},{"year":2018,"claim":"Characterized allosteric modulation within the transmembrane domain (PAM/NAM switching by methional) and broadened T1R3 physiology to gastric acid secretion, bone resorption, and retinal endothelial signaling.","evidence":"Interspecies chimeras, mutagenesis, and modeling defining TMD allosteric sites; siRNA/lactisole gastric proton assays; Tas1r3 mutant bone-marker and osteoclast analysis; T1R3 siRNA in retinal microvascular endothelium","pmids":["30087430","29665689","29019082","30353220"],"confidence":"Medium","gaps":["PAM/NAM allosteric sites localized to T1R1, not T1R3","Osteoclast-intrinsic mechanism only partially defined"]},{"year":2020,"claim":"Linked extraoral T1R3 to intestinal epithelial barrier and immune homeostasis, placing it upstream of oxidative stress/tight-junction disruption and required for tuft cell maintenance and type 2 immunity.","evidence":"T1R3 siRNA/claudin-3 rescue in Caco-2 cells with ROS measurement; Tas1r3-deficient mice with tuft cell counts and parasite/succinate immune responses","pmids":["32580504","31980480"],"confidence":"Medium","gaps":["Ligand driving tuft cell homeostatic signaling unidentified","Connection between barrier and tuft cell roles unclear"]},{"year":2024,"claim":"Provided a structural-binding model of steviol glycoside engagement across four sites of the T1R2/T1R3 heterodimer and proposed Gα C-terminus binding to the TMD shifting the receptor to a high-affinity state.","evidence":"Radioligand binding, computational docking to a homology model, and Gα protein binding assay","pmids":["39424933"],"confidence":"Medium","gaps":["Gα interaction not validated by mutagenesis","No experimental high-resolution structure"]},{"year":null,"claim":"How a single receptor subunit selects among Gq/Ca2+/ERK, Gαs/RhoA, and mTORC1 outputs across diverse extraoral tissues, and the experimental structures of its dimers in distinct ligand/effector states, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental high-resolution structure of T1R3-containing dimers","G-protein-independent route to mTORC1 unidentified","Tissue-specific determinants of output selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,5,19]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[9,16,22,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,34,40]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[20,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,41,33]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[1,9,19]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[16,32,36]}],"complexes":["T1R2/T1R3 sweet receptor heterodimer","T1R1/T1R3 umami receptor heterodimer","T1R3 homodimer"],"partners":["TAS1R2","TAS1R1","GNAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7RTX0","full_name":"Taste receptor type 1 member 3","aliases":["Sweet taste receptor T1R3"],"length_aa":852,"mass_kda":93.4,"function":"Putative taste receptor. TAS1R1/TAS1R3 responds to the umami taste stimulus (the taste of monosodium glutamate). TAS1R2/TAS1R3 recognizes diverse natural and synthetic sweeteners. TAS1R3 is essential for the recognition and response to the disaccharide trehalose (By similarity). Sequence differences within and between species can significantly influence the selectivity and specificity of taste responses","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q7RTX0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAS1R3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TAS1R3","total_profiled":1310},"omim":[{"mim_id":"609347","title":"RECEPTOR EXPRESSION-ENHANCING PROTEIN 2; REEP2","url":"https://www.omim.org/entry/609347"},{"mim_id":"606226","title":"TASTE RECEPTOR TYPE 1, MEMBER 2; TAS1R2","url":"https://www.omim.org/entry/606226"},{"mim_id":"606225","title":"TASTE RECEPTOR TYPE 1, MEMBER 1; TAS1R1","url":"https://www.omim.org/entry/606225"},{"mim_id":"605865","title":"TASTE RECEPTOR TYPE 1, MEMBER 3; TAS1R3","url":"https://www.omim.org/entry/605865"},{"mim_id":"139395","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-TRANSDUCING ACTIVITY POLYPEPTIDE 3; GNAT3","url":"https://www.omim.org/entry/139395"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"epididymis","ntpm":11.5},{"tissue":"lymphoid tissue","ntpm":3.4},{"tissue":"salivary gland","ntpm":7.4}],"url":"https://www.proteinatlas.org/search/TAS1R3"},"hgnc":{"alias_symbol":["T1R3"],"prev_symbol":[]},"alphafold":{"accession":"Q7RTX0","domains":[{"cath_id":"3.40.50.2300","chopping":"26-49_60-188_331-444","consensus_level":"high","plddt":89.2755,"start":26,"end":444},{"cath_id":"3.40.50.2300","chopping":"191-327_455-485","consensus_level":"high","plddt":90.864,"start":191,"end":485},{"cath_id":"1.20.1070.10","chopping":"568-827","consensus_level":"medium","plddt":90.1977,"start":568,"end":827},{"cath_id":"2.10.50","chopping":"508-557","consensus_level":"medium","plddt":88.7524,"start":508,"end":557}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7RTX0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7RTX0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7RTX0-F1-predicted_aligned_error_v6.png","plddt_mean":87.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TAS1R3","jax_strain_url":"https://www.jax.org/strain/search?query=TAS1R3"},"sequence":{"accession":"Q7RTX0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7RTX0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7RTX0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7RTX0"}},"corpus_meta":[{"pmid":"17724332","id":"PMC_17724332","title":"T1R3 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the Sac locus, the major determinant of sweet taste sensitivity differences between mouse strains. Sequence comparison across taster and non-taster strains identified a polymorphism (Ile60Thr) predicted to introduce an extra N-terminal glycosylation site in non-tasters that would interfere with receptor dimerization.\",\n      \"method\": \"Positional cloning, sequence analysis, structural modeling\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — positional cloning plus sequence polymorphism analysis in multiple strains; dimerization interference is structural prediction only, not experimentally confirmed in this paper\",\n      \"pmids\": [\"11326277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mice lacking T1R3 showed no preference for artificial sweeteners and had diminished (but not abolished) behavioral and nerve responses to sugars and umami compounds, demonstrating T1R3 is required for artificial sweetener detection but that T1R3-independent sweet/umami pathways also exist.\",\n      \"method\": \"T1R3 knockout mice; behavioral preference tests; chorda tympani nerve recordings\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout phenotype with both behavioral and electrophysiological readouts, widely replicated across subsequent studies\",\n      \"pmids\": [\"12869700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"T1R3 is essential for cellular recognition of the disaccharide trehalose, demonstrated using a heterologous expression system where T1R3 alone conferred responsiveness to trehalose.\",\n      \"method\": \"Heterologous expression assay in cell line\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single heterologous expression method, no mutagenesis confirmation\",\n      \"pmids\": [\"12892531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The cysteine-rich region (CRD) of human T1R3 determines species-specific sensitivity to sweet proteins brazzein, monellin, and thaumatin. Site-directed mutagenesis within the CRD of T1R3 affected receptor activity toward these proteins and overall receptor efficacy, identifying the CRD as an important ligand-interaction domain.\",\n      \"method\": \"Chimeric receptor expression, site-directed mutagenesis, heterologous expression assay in HEK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional validation in heterologous expression, multiple mutants tested, single lab\",\n      \"pmids\": [\"15299024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The transmembrane domain of human T1R3 is required for sweet receptor responsiveness to cyclamate. Alanine-scanning mutagenesis of the predicted transmembrane binding pocket identified six residues critical for cyclamate response; molecular modeling docked cyclamate within this pocket, and predicted overlap between cyclamate (agonist) and lactisole (inverse agonist) binding sites.\",\n      \"method\": \"Mixed-species chimeric receptors, directed mutagenesis, alanine scanning, molecular modeling, heterologous expression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic alanine-scanning mutagenesis combined with chimera analysis and molecular docking in a single rigorous study\",\n      \"pmids\": [\"16076846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Each subunit (T1R2 and T1R3) of the heteromeric sweet receptor independently binds sweet stimuli with distinct affinities and conformational changes. A single amino acid change in T1R3 associated with decreased sweet sensitivity in mice drastically reduced ligand affinities for T1R3, demonstrating that T1R3 expands the receptive range of the sweet receptor.\",\n      \"method\": \"Ligand binding assays with expressed N-terminal domain proteins, site-directed mutagenesis\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding assays with purified domains plus mutagenesis confirming functional role of specific residue, single lab\",\n      \"pmids\": [\"16271873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The ligand-binding N-terminal domain (NTD) of mouse T1R3 was expressed as fusion proteins in E. coli, purified, and shown to be properly folded and capable of binding ligands by spectroscopic analysis, establishing that the T1R3 NTD is a functional autonomous ligand-binding module.\",\n      \"method\": \"Heterologous protein expression (E. coli), column chromatography purification, circular dichroism spectroscopy, ligand binding assays\",\n      \"journal\": \"Chemical senses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution of domain with binding confirmation, single lab, limited ligand characterization\",\n      \"pmids\": [\"16621970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"T1R3 and the taste G protein gustducin, expressed in intestinal enteroendocrine cells, underlie luminal sugar sensing and regulation of SGLT1 mRNA and protein expression. Knockout mice lacking T1R3 or alpha-gustducin failed to upregulate SGLT1 in response to dietary sugars or artificial sweeteners, and artificial sweeteners acting on enteroendocrine GLUTag cells stimulated gut hormone secretion implicated in SGLT1 upregulation.\",\n      \"method\": \"T1R3 and alpha-gustducin knockout mice; SGLT1 mRNA/protein measurement; GLUTag cell stimulation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with molecular readout replicated in two KO lines plus in vitro enteroendocrine cell model\",\n      \"pmids\": [\"17724332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C/EBPbeta activates the human TAS1R3 promoter, as demonstrated by luciferase reporter assay and EMSA in bile duct carcinoma cells (HuCCT1). The proximal 226-bp upstream of ATG contains the core promoter activity.\",\n      \"method\": \"5'-RACE, luciferase reporter assay, EMSA\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional promoter assay plus EMSA, single lab, single cell line\",\n      \"pmids\": [\"17928076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"T1R3 functions as a gustatory calcium-magnesium receptor. Genome scan linked calcium/magnesium preference to the Tas1r3 locus; Tas1r3 knockout mice preferred calcium solutions avoided by wild-type mice; oral calcium elicited reduced chorda tympani nerve activity in Tas1r3 knockout mice. A V689A substitution unique to the PWK strain was associated with strong calcium/magnesium preference.\",\n      \"method\": \"Genome scan, congenic and knockout mice, chorda tympani nerve electrophysiology, two-bottle preference tests, sequence analysis\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic approaches (genome scan, congenic, knockout) with both behavioral and electrophysiological readouts\",\n      \"pmids\": [\"18593862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Two promoter SNPs at -1572 (rs307355) and -1266 (rs35744813) upstream of TAS1R3 reduce promoter activity as shown by luciferase reporter assay; the T allele of each SNP results in lower activity. A distal silencing element in the TAS1R3 promoter was also characterized, demonstrating transcriptional regulation of TAS1R3 expression.\",\n      \"method\": \"Luciferase reporter assay, human genetic association, population survey\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay corroborating genetic association; two independent SNPs tested with same directional effect\",\n      \"pmids\": [\"19559618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Direct binding of sweet agonists and antagonists to the full heterodimeric T1R2/T1R3 receptor in native membrane preparations was detected by saturation transfer difference (STD) NMR, allowing distinction between mutations affecting ligand-binding sites versus downstream signal transduction.\",\n      \"method\": \"Saturation transfer difference NMR spectroscopy on membrane preparations from HEK293 cells expressing sweet receptor\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct binding NMR on native membranes, single lab, no mutagenesis validation in same paper\",\n      \"pmids\": [\"19664591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Phenoxyauxin herbicides and lipid-lowering fibrates inhibit human T1R3 but not rodent T1R3, identifying these compounds as species-selective T1R3 inhibitors.\",\n      \"method\": \"Heterologous expression assay comparing human vs. rodent T1R3\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional receptor assay with species comparison, single lab\",\n      \"pmids\": [\"19817384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Key amino acid residues in brazzein (sites 1–3) and in the T1R2 Venus flytrap module are required for brazzein activation of the T1R2/T1R3 sweet receptor. Mutagenesis of receptor residue hT1R2:R217A selectively reduced brazzein activity and increased cooperativity for multiple ligands binding both subunits, implicating this site in subunit-subunit interaction rather than direct brazzein binding. Results support a multi-point interaction between brazzein and the sweet receptor not fitting the wedge model.\",\n      \"method\": \"Site-directed mutagenesis of brazzein and receptor subunits; HEK293 cell expression assay; human taste panel\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis of both ligand and receptor with functional in vitro assay plus human taste panel, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"20302879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"T1R3 knockout mice lacking T1R3 or alpha-gustducin failed to upregulate intestinal SGLT1 in response to sugars. T1R3-expressing taste cells in the tongue were shown by RT-PCR, qPCR, in situ hybridization, and immunohistochemistry to co-express GLUT4, SGLT1, and SUR1 (a KATP channel component), suggesting T1R3+ cells are equipped for metabolic glucose sensing independent of T1R2+T1R3.\",\n      \"method\": \"RT-PCR, quantitative PCR, in situ hybridization, immunohistochemistry, electrophysiological recording of KATP currents\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular methods plus electrophysiology, single lab\",\n      \"pmids\": [\"21383163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human TAS1R3 polymorphisms F749S and R757C in the transmembrane domain severely impair in vitro T1R1/T1R3 response to MSG, as demonstrated by functional expression. A molecular model of the ligand-binding region provides a mechanistic explanation consistent with the functional data.\",\n      \"method\": \"Functional expression of polymorphic receptors in heterologous cells, molecular modeling\",\n      \"journal\": \"Chemical senses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional expression of natural variants with phenotypic confirmation, corroborated by molecular model\",\n      \"pmids\": [\"21422378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"T1R1/T1R3 functions as a direct cell-surface sensor of amino acid availability that regulates mTORC1 activity. Knockdown of T1R1/T1R3 reduces amino acid-stimulated mTORC1 signaling, alters mTORC1 localization, downregulates pathway inhibitors, upregulates amino acid transporters, blocks translation initiation, and induces autophagy in mammalian cells.\",\n      \"method\": \"siRNA knockdown; mTORC1 signaling assays (phosphorylation readouts); autophagy assays; subcellular localization imaging\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal cellular assays with genetic knockdown, published in high-impact journal, subsequently replicated by multiple labs\",\n      \"pmids\": [\"22959271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"T1R3 homodimer functions as a glucose-sensing receptor in pancreatic β-cells. Sucralose (T1R3 agonist) increased intracellular ATP even in the absence of glucose, augmented mitochondrial metabolism, and shRNA knockdown of T1R3 attenuated glucose-induced ATP elevation and insulin secretion.\",\n      \"method\": \"Luciferase-based ATP biosensor in MIN6 cells, shRNA knockdown of T1R3, pharmacological agonism with sucralose and 3-O-methylglucose\",\n      \"journal\": \"Endocrine journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell ATP imaging plus knockdown with insulin secretion readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"24200979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"T1R2 and T1R3 are expressed in human and rat bladder urothelium. Saccharin augmented bladder smooth muscle contraction induced by electrical field stimulation only when urothelium was present; zinc (a T1R3 inhibitor) blocked this effect, indicating T1R3-dependent urothelial signaling mediates sweetener-augmented bladder contraction.\",\n      \"method\": \"Immunohistochemistry, immunoblotting, organ bath contractility assay with pharmacological inhibition\",\n      \"journal\": \"The Journal of urology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with urothelium-dependent functional assay, single lab\",\n      \"pmids\": [\"22019168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human T1R3 (hTAS1R3) expressed in HEK293 cells is activated by calcium, and this response is attenuated by lactisole (a T1R3 inhibitor). In trained human volunteers, lactisole reduced the perceived calcium intensity of calcium lactate, establishing T1R3 as a human calcium taste receptor.\",\n      \"method\": \"Heterologous expression (HEK293 transfection), pharmacological inhibition with lactisole, human psychophysical taste testing\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro receptor assay combined with human taste psychophysics with pharmacological blockade\",\n      \"pmids\": [\"22773945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human T1R3 surface membrane trafficking requires co-expression with human T1R2; human T1R3 alone is not trafficked to the membrane. The Venus flytrap module and cysteine-rich domain of human T1R3 contain regions that inhibit its membrane trafficking and coordinate its regulation. This is distinct from mouse T1r3, which reaches the membrane without T1r2.\",\n      \"method\": \"Tagged receptor expression in HEK293 cells, domain-swap chimeras, truncation mutants, cell surface localization assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic chimera/truncation analysis with direct membrane localization readout, single lab\",\n      \"pmids\": [\"25029362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The N-terminal domain (NTD) of human T1R3 was refolded from E. coli inclusion bodies, shown to behave as a dimer by size-exclusion chromatography, and demonstrated to bind sucralose with millimolar affinity by tryptophan fluorescence quenching and microcalorimetry.\",\n      \"method\": \"Recombinant protein expression in E. coli, refolding, size-exclusion chromatography, circular dichroism, tryptophan fluorescence quenching, isothermal titration calorimetry\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with biophysical binding measurements, single lab, no functional signaling validation\",\n      \"pmids\": [\"22450161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"T1R1-T1R3 expressed in intestinal enteroendocrine cells mediates CCK secretion in response to L-amino acids (Phe, Leu, Glu) but not Trp. siRNA knockdown of T1R1 in STC-1 cells reduced Phe-, Leu-, and Glu-stimulated CCK release; the T1R3 inhibitor gurmarin also blocked these responses, while the Ca2+-sensing receptor antagonist blocked only Trp-stimulated CCK secretion.\",\n      \"method\": \"siRNA knockdown of T1R1, pharmacological inhibition with gurmarin and NPS2143, CCK secretion assay in STC-1 cells and intestinal tissue explants\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic (siRNA) and pharmacological inhibition with specific physiological readout, tested in both cell line and ex vivo tissue\",\n      \"pmids\": [\"23203156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"T1R1/T1R3 exhibits species-dependent ligand specificity determined by 12 key residues in the Venus flytrap domain of T1R1. Residues critical for human-type acidic amino acid recognition are at the orthosteric binding site, while residues mediating mouse-type broad responses are outside both orthosteric and IMP allosteric sites, demonstrating two distinct determinants of ligand specificity.\",\n      \"method\": \"Chimeric human-mouse receptor analysis, site-directed mutagenesis, heterologous expression functional assays, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic chimera and mutagenesis study with functional assays identifying two distinct molecular mechanisms, single lab\",\n      \"pmids\": [\"24214976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"L-theanine activates the T1R1+T1R3 umami receptor and shows synergy with IMP. Site-directed mutagenesis demonstrated that L-theanine binds to the L-amino acid binding site in the Venus flytrap domain of T1R1.\",\n      \"method\": \"Heterologous expression functional assay, site-directed mutagenesis, IMP synergy assay\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with functional assay confirming binding site, single lab\",\n      \"pmids\": [\"24633359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"T1R1/T1R3 activation by luminal MSG or L-cysteine initiates the peristaltic reflex (ascending contraction, descending relaxation) and CGRP release in rat colon flat-sheet preparations. IMP augmented these effects. In T1R1 knockout mice, mucosal stroking but not MSG elicited a peristaltic reflex. MSG also enhanced fecal pellet propulsion velocity in guinea pig distal colon.\",\n      \"method\": \"T1R1 knockout mice; three-chamber flat-sheet colon preparation; electrophysiology; CGRP release assay; video recording of pellet propulsion\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout plus pharmacological and ex vivo functional readouts in multiple species/preparations\",\n      \"pmids\": [\"25324508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mouse neutrophils express functional T1R1/T1R3: stimulation with L-alanine or L-serine (umami receptor ligands) elicited ERK/p38 MAPK phosphorylation and chemotactic migration, and reduced LPS-induced cytokine production (TNF-α) through inhibition of NF-κB and STAT3 phosphorylation.\",\n      \"method\": \"RNA sequencing, qRT-PCR, signaling assays (ERK/p38 phosphorylation), chemotaxis assay, cytokine measurement, NF-κB/STAT3 activity assay\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional assays in primary neutrophils, single lab, no receptor knockdown control shown\",\n      \"pmids\": [\"25301019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Lactisole inhibits the mouse glucose-sensing T1R3 receptor in MIN6 pancreatic β-cells. Lactisole attenuated sweetener-induced Ca2+ elevation and insulin secretion, and inhibited glucose-induced elevations of NADH, ATP, and insulin secretion. In HEK293 cells stably expressing mouse T1R3, lactisole attenuated sucralose-induced Ca2+ elevation but not cAMP elevation.\",\n      \"method\": \"Pharmacological inhibition assay in MIN6 cells, stably transfected HEK293-T1R3 cells, intracellular Ca2+/cAMP/NADH/ATP measurements, insulin secretion assay in mouse islets\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays plus ex vivo islet experiments, single lab\",\n      \"pmids\": [\"25994004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Muscle regulatory factors MyoD and Myogenin bind the evolutionarily conserved T1R3 promoter and regulate T1R3 expression; T1R3 expression increases with C2C12 myoblast differentiation. A repressive element upstream of the human T1R3 promoter was also identified.\",\n      \"method\": \"Comparative genomics, luciferase reporter assay, identification of binding sites for MyoD/Myogenin, qPCR of T1R3 expression during differentiation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional promoter assay with transcription factor identification, single lab\",\n      \"pmids\": [\"26545778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tas1r3 knockout mice showed reduced insulin sensitivity and impaired glucose tolerance following intraperitoneal or intragastric glucose administration, with impairment worsening with age after IP but not IG administration, indicating extraoral T1R3 (likely pancreatic/brain) has a role in glucose homeostasis independent of incretin effects (incretin responses were similar between KO and WT).\",\n      \"method\": \"Tas1r3 knockout mice; glucose and insulin tolerance tests; behavioral sucrose preference tests; incretin measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with multiple metabolic assays and control experiments ruling out incretin mechanism, single lab\",\n      \"pmids\": [\"26107521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In C2C12 myotubes, methionine activates mTORC1 through the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 signaling axis. T1R1 and T1R3 are expressed in these cells, and methionine was the most potent amino acid among those tested in activating this pathway.\",\n      \"method\": \"siRNA knockdown of T1R1/T1R3, intracellular Ca2+ measurement, ERK1/2 phosphorylation assay, mTORC1 activation assay, protein synthesis measurement\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with multiple signaling readouts, single lab\",\n      \"pmids\": [\"27727170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"T1R3 is expressed in the pulmonary vasculature. Sucralose (T1R3 agonist) attenuated LPS- and thrombin-induced endothelial barrier dysfunction and bacteria-induced lung edema in vivo. Protective effects were blocked by T1R3 siRNA or G-protein siRNA. Sucralose reduced LPS-induced Src, PAK, MLC2, HSP27, and p110αPI3K phosphorylation/expression.\",\n      \"method\": \"T1R3 siRNA knockdown, endothelial barrier permeability assay, in vivo lung edema model, signaling assays (Src/PAK/MLC2/HSP27/PI3K)\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with both in vitro and in vivo functional readouts plus downstream signaling characterization, single lab\",\n      \"pmids\": [\"28971978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"T1R1/T1R3 modulates the mTOR pathway in mouse mammary gland in vivo to regulate milk protein (β-casein) synthesis. T1R1 knockout reduced total milk yield and β-casein synthesis, decreased phosphorylation of 4EBP1 and S6K, and increased AA transporter (SLC3A2, SLC7A5, SLC1A5) expression.\",\n      \"method\": \"T1R1 knockout mice (mammary gland), weigh-suckle-weigh milk yield, qPCR, western blot of mTOR pathway\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with multiple molecular and physiological readouts, single lab\",\n      \"pmids\": [\"28497545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"T1R3 homomeric sweet receptor negatively regulates adipogenesis through a Gαs-mediated but cAMP-independent mechanism. Sucralose/saccharin-induced T1R3 activation caused microtubule disassembly (blocked by dominant-negative Gαs), activated RhoA/ROCK through GEF-H1, and dominant-negative RhoA blocked sweetener-induced Akt dephosphorylation and suppression of PPARγ/C/EBPα.\",\n      \"method\": \"Dominant-negative/constitutively-active Gαs overexpression, RhoA dominant-negative mutants, GEF-H1 knockdown, microtubule staining, Akt/PPARγ/C/EBPα signaling assays in 3T3-L1 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic interventions (dominant negatives, knockdowns) with signaling readouts in single cell model, single lab\",\n      \"pmids\": [\"28472098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Methional, a flavor compound, acts as a positive allosteric modulator (PAM) of human T1R1/T1R3 and a negative allosteric modulator (NAM) of mouse T1R1/T1R3. Interspecies chimeric receptor analysis demonstrated methional interacts with the transmembrane domain of T1R1 (not the extracellular domain). Site-directed mutagenesis and molecular modeling identified two distinct binding sites in the T1R1 transmembrane domain and showed that residues at the bottom of the allosteric pocket determine PAM vs. NAM switching.\",\n      \"method\": \"Interspecies chimeric receptors, site-directed mutagenesis, heterologous expression functional assay, molecular modeling\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chimera analysis, mutagenesis, and molecular modeling in single study identifying mechanism of PAM/NAM switching, multiple orthogonal methods\",\n      \"pmids\": [\"30087430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cyclamate and acesulfame K modulate proton secretion in human gastric parietal cells (HGT-1) through T1R3. T1R3 siRNA knockdown and co-treatment with lactisole (T1R3 inhibitor) reduced the effect of both sweeteners and d-threonine on proton release, establishing T1R3 as a key mediator of gastric acid secretion responses to these compounds.\",\n      \"method\": \"TAS1R3 siRNA knockdown, pharmacological inhibition with lactisole, intracellular pH assay, RT-qPCR, immunocytochemistry\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus pharmacological inhibition converging on same phenotype, single lab\",\n      \"pmids\": [\"29665689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Val and Met activate mTOR signaling in bovine mammary epithelial cells through TAS1R1/TAS1R3, elevating intracellular calcium. TAS1R1 siRNA knockdown reduced Val- and Met-induced intracellular Ca2+ elevation, decreased mTOR/S6K1/4EBP1 phosphorylation, and reduced β-casein (CSN2) mRNA abundance.\",\n      \"method\": \"siRNA knockdown of TAS1R1 in primary bovine mammary epithelial cells and Mac-T cells, intracellular Ca2+ measurement, western blot of mTOR pathway, qPCR\",\n      \"journal\": \"Journal of dairy science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with Ca2+ and mTOR pathway readouts in primary cells, single lab\",\n      \"pmids\": [\"30268610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Artificial sweeteners sucralose and aspartame increased intestinal epithelial permeability and downregulated claudin-3 at the cell surface; T1R3 knockdown attenuated these effects. Aspartame induced ROS production to cause permeability and claudin-3 internalization; claudin-3 overexpression rescued sweetener-induced permeability, placing T1R3 upstream of oxidative stress and tight junction disruption.\",\n      \"method\": \"T1R3 siRNA knockdown in Caco-2 cells, epithelial permeability assay, claudin-3 surface localization, ROS measurement, claudin-3 overexpression rescue\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown and overexpression rescue with multiple cellular readouts, single lab\",\n      \"pmids\": [\"32580504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TAS1R3 is required for normal tuft cell homeostasis in the distal small intestine. Tas1r3-deficient mice had a severe decrease in distal small intestinal tuft cells at homeostasis, and both BALB/c mice (bearing inactive TAS1R3) and Tas1r3-deficient C57BL6/J mice had severely impaired type 2 immune responses to the protozoa Tritrichomonas muris and succinate in the ileum.\",\n      \"method\": \"Tas1r3 knockout mice, tuft cell counting, parasite infection model, immune response measurement\",\n      \"journal\": \"ImmunoHorizons\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with cellular and immune phenotype, corroborated in two genetically distinct mouse models\",\n      \"pmids\": [\"31980480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"T1R3 is expressed in primary osteoclasts (confirmed by expression correlation with differentiation status) and its loss in Tas1r3 mutant mice is associated with >60% reduction in the bone resorption marker collagen type I C-telopeptide, while bone formation marker PINP is unchanged, indicating TAS1R3 influences bone remodeling primarily through osteoclast function.\",\n      \"method\": \"Tas1r3 mutant mice, serum bone marker assays (PINP, CTX-I), primary osteoclast culture with qPCR\",\n      \"journal\": \"Journal of physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo knockout phenotype with systemic marker readout, mechanistic pathway only partially defined, single lab\",\n      \"pmids\": [\"29019082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Steviol glycosides bind to four distinct sites on the T1R2/T1R3 heterodimer: VFD2, VFD3, TMD2, and TMD3. The C20 carboxy terminus of the Gα protein binds the intracellular region of either TMD2 or TMD3, shifting the receptor to a high-affinity state for steviol glycosides. Lactisole (negative allosteric modulator) binding sites overlap with tested ligand sites.\",\n      \"method\": \"Radioligand binding experiments, computational docking to homology model, Gα protein binding assay\",\n      \"journal\": \"Communications chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — binding experiments plus computational docking, Gα interaction identified but not validated by mutagenesis, single lab\",\n      \"pmids\": [\"39424933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Amino acids differentially regulate ERK1/2 and mTORC1 through T1R1/T1R3 in MIN6 pancreatic β-cells via distinct signaling pathways. Ca2+ entry is required for ERK1/2 but not mTORC1 activation; Gq (inhibited by UBO-QIC) is required for ERK1/2 but not mTORC1; pertussis toxin (Gi inhibitor) blocked neither pathway; amino acids did not affect cAMP, excluding Gs.\",\n      \"method\": \"Pharmacological inhibition of Gi (pertussis toxin), Gq (UBO-QIC), Gs (cAMP measurement), Ca2+ chelation; ERK1/2 and mTORC1 phosphorylation assays in MIN6 cells\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic pharmacological dissection of G-protein pathway with multiple readouts, single lab\",\n      \"pmids\": [\"26168033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Activation of retinal microvascular endothelial T1R3 (but not T1R2) by sucralose attenuated VEGF-induced cell proliferation, migration, adhesion, tube formation, and Akt phosphorylation. T1R3 siRNA knockdown abolished these protective effects.\",\n      \"method\": \"T1R3 siRNA knockdown in RMVEC cells, proliferation/migration/adhesion/tube formation assays, Akt phosphorylation western blot\",\n      \"journal\": \"Graefe's archive for clinical and experimental ophthalmology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with multiple functional vasculogenic readouts plus signaling, single lab\",\n      \"pmids\": [\"30353220\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TAS1R3 (T1R3) is a class C GPCR subunit that obligatorily heterodimerizes with T1R2 (sweet receptor) or T1R1 (umami receptor), contributing distinct ligand-binding sites: the cysteine-rich domain binds sweet proteins, the transmembrane domain binds cyclamate and serves as an allosteric modulation site (including for lactisole inhibition), and the N-terminal Venus flytrap domain can independently bind ligands; beyond taste cells, extraoral T1R3 homodimers or T1R1/T1R3 heterodimers function as nutrient/amino acid sensors that couple through Gq/Ca2+/ERK and mTORC1 pathways to regulate SGLT1 expression, insulin secretion, CCK secretion, peristalsis, autophagy, milk protein synthesis, tuft cell homeostasis, bone resorption, and endothelial barrier function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TAS1R3 (T1R3) is a class C G protein-coupled receptor subunit that functions as the shared partner of the heteromeric sweet (T1R2/T1R3) and umami (T1R1/T1R3) taste receptors, and as the major genetic determinant of mouse sweet-taste sensitivity encoded by the Sac locus [#0, #1]. Genetic ablation of T1R3 abolishes preference for artificial sweeteners and diminishes responses to sugars and umami compounds, while leaving residual T1R3-independent sweet/umami signaling intact [#1]. Within these heterodimers, T1R3 contributes distinct, spatially separable ligand-interaction surfaces: its cysteine-rich domain governs species-specific recognition of sweet proteins such as brazzein, monellin, and thaumatin [#3]; its transmembrane domain houses the cyclamate agonist pocket that overlaps the lactisole inhibitor site [#4]; and its N-terminal Venus flytrap domain is an autonomous, dimerizing module that independently binds sweet ligands with distinct affinity, thereby expanding the receptor's receptive range [#5, #6, #21]. T1R3 also serves directly as a gustatory calcium-magnesium receptor in both mouse and human [#9, #19]. Beyond taste cells, extraoral T1R1/T1R3 and T1R3 homodimers act as nutrient and amino-acid sensors that couple, via Gq/Ca2+/ERK signaling, to the mTORC1 pathway: T1R1/T1R3 regulates amino-acid-stimulated mTORC1 activity, translation, and autophagy [#16, #41], drives milk protein synthesis in mammary epithelium [#32, #36], and underlies enteroendocrine sugar sensing and SGLT1 upregulation [#7]. T1R3-dependent signaling further mediates intestinal CCK secretion, colonic peristalsis, pancreatic insulin secretion and glucose homeostasis, gastric acid secretion, tuft cell homeostasis, osteoclast-driven bone resorption, and endothelial barrier integrity [#22, #25, #17, #29, #35, #38, #39, #31]. Human T1R3 surface trafficking is obligately dependent on co-expression with T1R2, distinguishing it from mouse T1r3 [#20]. Its expression is transcriptionally controlled by C/EBPβ and the myogenic factors MyoD/Myogenin, and modulated by promoter polymorphisms [#8, #28, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the molecular identity of the sweet-taste determinant by mapping the Sac locus to a GPCR gene, transforming a classical genetic trait into a defined receptor.\",\n      \"evidence\": \"Positional cloning and cross-strain sequence analysis identifying a dimerization-relevant polymorphism\",\n      \"pmids\": [\"11326277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dimerization interference was a structural prediction, not experimentally confirmed\", \"Did not define ligand-binding mechanism or signaling partners\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated genetically that T1R3 is required for artificial sweetener detection and contributes to sugar/umami sensing, while revealing that parallel T1R3-independent pathways also exist.\",\n      \"evidence\": \"T1R3 knockout mice with behavioral preference tests and chorda tympani nerve recordings\",\n      \"pmids\": [\"12869700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the residual T1R3-independent sweet/umami pathway\", \"Did not resolve which dimer partner mediates which modality\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Localized species-specific sweet-protein recognition to a discrete T1R3 domain, beginning the dissection of T1R3's modular ligand-binding architecture.\",\n      \"evidence\": \"Chimeric receptors and CRD site-directed mutagenesis in HEK cells\",\n      \"pmids\": [\"15299024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether CRD binds sweet proteins directly versus allosterically\", \"No structural model of the protein-receptor interface\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Assigned distinct ligand-binding roles to separate T1R3 domains, showing the transmembrane domain binds cyclamate (overlapping the lactisole site) and the N-terminal domain independently binds ligands to broaden the receptor's range.\",\n      \"evidence\": \"Alanine-scanning and chimera mutagenesis with molecular docking; N-terminal-domain binding assays plus mutagenesis\",\n      \"pmids\": [\"16076846\", \"16271873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise allosteric coupling between TMD and signal output unresolved\", \"Conformational changes inferred indirectly\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Confirmed the T1R3 N-terminal domain is an autonomous, properly folded ligand-binding module by reconstituting it in isolation.\",\n      \"evidence\": \"E. coli expression, purification, circular dichroism, and ligand binding of mouse T1R3 NTD\",\n      \"pmids\": [\"16621970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited ligand panel tested\", \"No coupling to downstream signaling demonstrated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended T1R3 function beyond the tongue, showing intestinal T1R3/gustducin sense luminal sugars and sweeteners to regulate SGLT1 expression and gut hormone secretion.\",\n      \"evidence\": \"T1R3 and alpha-gustducin knockout mice with SGLT1 readouts plus GLUTag enteroendocrine cell assays\",\n      \"pmids\": [\"17724332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intermediate signaling between receptor and SGLT1 transcription not fully mapped\", \"Did not define the dimer composition of the enteroendocrine sensor\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified T1R3 as a gustatory calcium-magnesium receptor, expanding its ligand repertoire beyond sweet/umami compounds.\",\n      \"evidence\": \"Genome scan, congenic and knockout mice, nerve electrophysiology, and behavioral preference tests\",\n      \"pmids\": [\"18593862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site for divalent cations on T1R3 not localized\", \"Dimer requirement for calcium sensing unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved transcriptional and biophysical features of T1R3, mapping functional promoter SNPs/silencer elements and detecting direct agonist/antagonist binding to the native heterodimer.\",\n      \"evidence\": \"Luciferase reporter assays with human genetics; saturation transfer difference NMR on native membranes; species-selective inhibitor screening\",\n      \"pmids\": [\"19559618\", \"19664591\", \"19817384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NMR lacked in-paper mutagenesis to assign binding sites\", \"Functional consequence of promoter SNPs in vivo not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Refined the brazzein-receptor interaction model, implicating a T1R2 residue in subunit-subunit cooperativity rather than direct binding and arguing against a simple wedge model.\",\n      \"evidence\": \"Mutagenesis of both ligand and receptor subunits with HEK293 assays and human taste panel\",\n      \"pmids\": [\"20302879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of multi-point interaction not solved\", \"Allosteric cooperativity mechanism inferred functionally\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that natural human transmembrane-domain polymorphisms impair umami (MSG) responses and that T1R3+ taste cells co-express metabolic glucose-sensing machinery.\",\n      \"evidence\": \"Functional expression of polymorphic receptors with modeling; multi-method expression profiling and KATP electrophysiology in taste cells\",\n      \"pmids\": [\"21422378\", \"21383163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether T1R3+ metabolic sensing is independent of T1R2/T1R3 not definitively shown\", \"Polymorphism effects not validated in human psychophysics\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established T1R1/T1R3 as a cell-surface amino-acid sensor controlling mTORC1, autophagy, and translation, and defined extraoral roles in insulin secretion, CCK release, bladder contraction, calcium taste, and human T1R2-dependent trafficking.\",\n      \"evidence\": \"siRNA/shRNA knockdown with mTORC1, autophagy, ATP, insulin, and CCK readouts; HEK293 expression with human taste psychophysics; chimera/truncation trafficking analysis; in vitro NTD biophysics\",\n      \"pmids\": [\"22959271\", \"24200979\", \"22019168\", \"22773945\", \"20220\", \"23203156\", \"22450161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct amino-acid binding to T1R1/T1R3 versus indirect sensing not fully resolved\", \"Mechanism linking receptor to mTORC1 relocalization undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped two distinct molecular determinants of species-dependent umami ligand specificity within the T1R1 Venus flytrap domain, one orthosteric and one outside known binding sites.\",\n      \"evidence\": \"Human-mouse chimeras, site-directed mutagenesis, functional assays, and molecular modeling\",\n      \"pmids\": [\"24214976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the non-orthosteric determinant unknown\", \"Contribution of T1R3 residues to specificity not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined umami ligand binding (L-theanine) at the T1R1 Venus flytrap site and extended T1R1/T1R3 signaling to colonic peristalsis and neutrophil chemotaxis/immunomodulation.\",\n      \"evidence\": \"Mutagenesis with functional and IMP-synergy assays; T1R1 knockout colon preparations with electrophysiology and CGRP assays; neutrophil signaling/chemotaxis assays\",\n      \"pmids\": [\"24633359\", \"25324508\", \"25301019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neutrophil study lacked receptor knockdown control\", \"Downstream coupling from receptor to peristaltic reflex incompletely mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Dissected the G-protein logic of extraoral T1R1/T1R3 signaling, showing Gq/Ca2+ drive ERK1/2 while mTORC1 activation is Gq- and Ca2+-independent, and defined transcriptional control by myogenic factors.\",\n      \"evidence\": \"Pharmacological G-protein dissection and phosphorylation assays in MIN6 cells; lactisole inhibition of glucose-sensing T1R3; promoter/transcription-factor reporter assays during myoblast differentiation\",\n      \"pmids\": [\"26168033\", \"25994004\", \"26545778\", \"26107521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The G-protein-independent route to mTORC1 not identified\", \"Tissue specificity of transcriptional regulators not established in vivo\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified divergent G-protein outputs of homomeric T1R3 (Gαs-mediated, cAMP-independent control of adipogenesis via RhoA/microtubules) and extended T1R3 to milk protein synthesis and endothelial barrier protection.\",\n      \"evidence\": \"Dominant-negative Gαs/RhoA and GEF-H1 knockdown in 3T3-L1 cells; T1R1 knockout mammary gland; T1R3/G-protein siRNA in pulmonary endothelium with in vivo edema models\",\n      \"pmids\": [\"28472098\", \"28497545\", \"28971978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a single receptor selects Gq versus Gαs outputs across tissues is unresolved\", \"Adipogenesis mechanism shown in a single cell model\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterized allosteric modulation within the transmembrane domain (PAM/NAM switching by methional) and broadened T1R3 physiology to gastric acid secretion, bone resorption, and retinal endothelial signaling.\",\n      \"evidence\": \"Interspecies chimeras, mutagenesis, and modeling defining TMD allosteric sites; siRNA/lactisole gastric proton assays; Tas1r3 mutant bone-marker and osteoclast analysis; T1R3 siRNA in retinal microvascular endothelium\",\n      \"pmids\": [\"30087430\", \"29665689\", \"29019082\", \"30353220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PAM/NAM allosteric sites localized to T1R1, not T1R3\", \"Osteoclast-intrinsic mechanism only partially defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked extraoral T1R3 to intestinal epithelial barrier and immune homeostasis, placing it upstream of oxidative stress/tight-junction disruption and required for tuft cell maintenance and type 2 immunity.\",\n      \"evidence\": \"T1R3 siRNA/claudin-3 rescue in Caco-2 cells with ROS measurement; Tas1r3-deficient mice with tuft cell counts and parasite/succinate immune responses\",\n      \"pmids\": [\"32580504\", \"31980480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand driving tuft cell homeostatic signaling unidentified\", \"Connection between barrier and tuft cell roles unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided a structural-binding model of steviol glycoside engagement across four sites of the T1R2/T1R3 heterodimer and proposed Gα C-terminus binding to the TMD shifting the receptor to a high-affinity state.\",\n      \"evidence\": \"Radioligand binding, computational docking to a homology model, and Gα protein binding assay\",\n      \"pmids\": [\"39424933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gα interaction not validated by mutagenesis\", \"No experimental high-resolution structure\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor subunit selects among Gq/Ca2+/ERK, Gαs/RhoA, and mTORC1 outputs across diverse extraoral tissues, and the experimental structures of its dimers in distinct ligand/effector states, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental high-resolution structure of T1R3-containing dimers\", \"G-protein-independent route to mTORC1 unidentified\", \"Tissue-specific determinants of output selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 5, 19]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [9, 16, 22, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 34, 40]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [20, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 41, 33]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [1, 9, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16, 32, 36]}\n    ],\n    \"complexes\": [\n      \"T1R2/T1R3 sweet receptor heterodimer\",\n      \"T1R1/T1R3 umami receptor heterodimer\",\n      \"T1R3 homodimer\"\n    ],\n    \"partners\": [\n      \"TAS1R2\",\n      \"TAS1R1\",\n      \"GNAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}