TAS2R38 is a human gene located on chromosome 7q34 that encodes the taste receptor type 2 member 38 (T2R38), a seven-transmembrane G protein-coupled receptor primarily responsible for detecting bitter-tasting compounds such as phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP).[1][2] The T2R38 protein, consisting of 333 amino acids, is expressed on the surface of taste receptor cells in the tongue, where it activates downstream signaling pathways involving gustducin and TRPM5 to mediate the perception of bitterness from glucosinolates and related thiourea compounds.[1][2] This receptor belongs to the larger TAS2R family of approximately 25 bitter taste receptors, which collectively enable the detection of potentially toxic substances in food.[1]Genetic variation in TAS2R38 significantly influences individual differences in bitter taste sensitivity, with three key single nucleotide polymorphisms (rs713598, rs1726866, and rs10246939) defining common haplotypes: the PAV (proline-alanine-valine) variant associated with enhanced tasting ability and the AVI (alanine-valine-isoleucine) variant linked to reduced or absent sensitivity.[3] These polymorphisms exhibit autosomal dominant inheritance for the taster phenotype and contribute to population-level differences in dietary preferences, potentially affecting intake of vegetables rich in glucosinolates like broccoli.[1][3] Beyond its role in gustation, TAS2R38 is expressed in extraoral tissues, including airway epithelial cells and the gastrointestinal tract, where it senses bacterial quorum-sensing molecules and modulates innate immune responses, such as nitric oxide production to combat respiratory infections.[4] The PAV haplotype has been associated with more efficient immune function and lower susceptibility to chronic rhinosinusitis, while the AVI variant correlates with increased infection risk.[4]Research has also linked TAS2R38 variants to broader health outcomes, including a potential role in nicotine dependence and alcohol consumption patterns, as bitter taste sensitivity may influence avoidance of these substances.[1] In studies of exceptional longevity, such as among centenarians in Sardinia, the PAV/PAV genotype shows higher prevalence, suggesting contributions to extended lifespan through enhanced dietary choices and immune protection.[4] Additionally, TAS2R38 expression in the testis and associations with conditions like dental caries highlight its multifaceted physiological roles.[2]
Gene Overview
Genomic Location and Structure
The TAS2R38 gene is located on the long arm of human chromosome 7 at cytogenetic band 7q34, specifically spanning positions 141,972,631 to 141,973,773 on the reverse strand according to the GRCh38.p14 assembly.[5] This positions the gene within a compact genomic region of approximately 1.1 kb, consistent with the typical architecture of taste receptor genes.[6] The official Ensembl gene identifier is ENSG00000257138, reflecting current annotation standards.[6]The gene structure of TAS2R38 is notably simple, consisting of a single exon that encodes the entire open reading frame without intervening introns in the coding region—a characteristic feature of many TAS2R family members.[1] The coding sequence measures 1,002 base pairs, which translates to a 333-amino-acid protein product.[1] This intronless design facilitates efficient transcription and minimizes alternative splicing, ensuring a straightforward genetic blueprint for the bitter taste receptor.[7]TAS2R38 forms part of a clustered array of TAS2R genes on chromosome 7, which collectively encode over a dozen bitter taste receptors in humans.[8] This genomic organization underscores the evolutionary expansion of the TAS2R family, with TAS2R38 showing high sequence homology to orthologs in other primates, such as chimpanzees and rhesus macaques, indicating conserved functional roles in bitter perception across species.[9] The UniProt accession for the encoded protein is P59533, linking the genomic sequence to its functional annotation.[10]
Transcription and Regulation
The transcription of the TAS2R38 gene is regulated by its promoter region, which features binding sites for several transcription factors, including AML1a, ATF-2, and c-Jun, as identified through computational predictions of regulatory elements.[2] These factors likely contribute to the tissue-specific initiation of transcription in taste receptor cells, where TAS2R38 mRNA expression correlates with individual variations in bitter taste perception.[11]Epigenetic mechanisms play a key role in modulating TAS2R38 expression. In taste cells, inflammation induced by lipopolysaccharide (LPS) increases chromatin accessibility at Tas2r promoters, including TAS2R38, leading to upregulated gene expression and heightened bitter taste sensitivity.[12] Histone modifications also influence basal TAS2R38 expression, with inflammatory signals promoting chromatin accessibility that enhances transcription in lingual epithelia.[13] Such epigenetic changes provide a link between environmental stressors and altered taste receptor function without altering the underlying DNA sequence.[14]TAS2R38 expression is upregulated as taste buds differentiate, coinciding with the maturation of type II taste receptor cells that express bitter receptors.Inflammatory pathways can alter epigenetic landscapes in taste tissues.[12]
Protein Structure and Function
Receptor Architecture
The TAS2R38 protein is a 333-amino acid polypeptide with a calculated molecular weight of 37.9 kDa, exhibiting the canonical seven-transmembrane helical topology of G protein-coupled receptors (GPCRs) within the taste 2 receptor subfamily.[2][10] This architecture includes an extracellular N-terminal domain, three intracellular loops, three extracellular loops, and an intracellular C-terminal tail, facilitating membrane integration and ligand sensing in taste cells.[15]Key structural features encompass the transmembrane helices (TM1–TM7), which form a bundle essential for receptor stability and function, with the N-terminus oriented extracellularly for potential ligand access and the C-terminus intracellularly, containing residues amenable to regulatory phosphorylation.[16] Unlike classical class A GPCRs, TAS2R38 lacks a fully conserved DRY motif at the TM3 intracellular end, reflecting adaptations in the taste receptor subfamily for specialized activation mechanisms.[17]Due to the absence of an experimentally determined crystal structure for TAS2R38, structural insights derive from homology models built on rhodopsin-like GPCRs, such as bovine rhodopsin (PDB: 1U19), revealing a ligand-binding pocket primarily within the transmembrane bundle involving TM3, TM6, and TM7, as well as contributions from extracellular loop 2 (ECL2).[16][15] These models highlight key residues like Asn103^{3.36} and Ser259^{6.47} (Ballesteros-Weinstein numbering) that line the orthosteric site, enabling recognition of bitter agonists.[16]Post-translational modifications include N-linked glycosylation at a conserved asparagine residue in ECL2 (Asn178), which supports proper receptor trafficking and maturation, and additional sites such as Asn89 on the N-terminus.[18][2] Palmitoylation on cysteine residues in the C-terminal tail aids membrane anchoring, a common feature in GPCRs to stabilize intracellular interactions, though specific sites in TAS2R38 remain to be fully characterized.[15]
Signal Transduction Mechanism
Upon binding of a bitter ligand to TAS2R38, the receptor undergoes a conformational change that facilitates coupling with the heterotrimeric G-protein gustducin, leading to its dissociation into the α-gustducin-GTP subunit and the βγ complex.00480-2) The liberated α-gustducin-GTP subunit then activates phospholipase C-β2 (PLC-β2), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).[19]00071-0)IP3 diffuses to the endoplasmic reticulum (ER), where it binds to IP3 receptors, triggering the release of Ca²⁺ from intracellular stores into the cytoplasm.[19] The resulting elevation in cytosolic Ca²⁺ concentration activates the transient receptor potential channel TRPM5, permitting Na⁺ influx that depolarizes the taste receptor cell membrane.00071-0)This depolarization promotes the opening of voltage-gated channels and culminates in the release of neurotransmitters from the taste cell, primarily ATP via CALHM1 channels, which transmits the signal to afferent nerves and adjacent cells; in turn, ATP can stimulate nearby presynaptic cells to release serotonin, providing feedback inhibition to modulate the gustatory response.[20] Concurrently, the α-gustducin pathway modulates cyclic AMP (cAMP) levels through activation of phosphodiesterase (PDE), which hydrolyzes cAMP to its inactive form 5'-AMP, providing feedback inhibition that fine-tunes signal amplification by preventing excessive adenylyl cyclase activity and sustaining low basal cAMP for optimal Ca²⁺ signaling.[19]87972-1/fulltext)
Ligands and Binding
Primary Agonists
The primary agonists of the TAS2R38 bitter taste receptor are phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), synthetic compounds characterized by thioamide structures that directly activate the receptor with high potency. Functional assays in HEK293 cells transiently transfected with the sensitive PAV variant of TAS2R38 demonstrate robust calcium mobilization in response to these ligands, confirming their role as canonical activators. The half-maximal effective concentration (EC50) for PTC is 1.1 μM, while for PROP it is 2.1 μM, indicating submicromolar to low micromolar sensitivity.[21]Binding specificity arises from targeted interactions between the agonists' sulfur-containing thioamide groups and the receptor's orthosteric site, particularly hydrogen bonding with asparagine at position 103 (Asn103). Hydrophobic π-π stacking further stabilizes binding through contacts with phenylalanine residues at positions 197 and 264, as well as tryptophan at 201, enabling selective recognition of these structural motifs. These molecular details, derived from computational modeling validated against experimental data, underscore TAS2R38's evolutionary adaptation to detect thioamide-based bitterants.[22]Dose-response profiles from calcium imaging experiments exhibit sigmoidal activation curves, with threshold detection in the nanomolar range and maximal responses at concentrations above 10 μM, reflecting efficient G protein-coupled signaling initiation upon agonist occupancy. Synthetic analogs such as goitrin, derived from glucosinolate hydrolysis in plants like cabbage, also serve as potent activators, though with reduced affinity (EC50 ≈ 65 μM), extending the receptor's responsiveness to structurally related natural products.
Other Substrates
Beyond its primary agonists like phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), TAS2R38 recognizes microbial quorum-sensing molecules, particularly acyl-homoserine lactones (AHLs) produced by gram-negative bacteria such as Pseudomonas aeruginosa. These include N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL, also known as AHL-12), which acts as a weak agonist with activation thresholds typically exceeding 10 μM EC50, enabling detection of bacterial biofilms in non-oral tissues like the respiratory epithelium.[23][24] This recognition supports innate immune responses by triggering localized defenses against pathogens.[25]TAS2R38 also interacts with dietary compounds from cruciferous vegetables, including glucosinolates such as sinigrin and their myrosinase-hydrolysis products like allyl isothiocyanate (AITC). Sinigrin binds to TAS2R38, contributing to the perceived bitterness of Brassica species (e.g., broccoli, cabbage), with sensitivity modulated by common TAS2R38 polymorphisms that alter receptor functionality and detection thresholds.[26] Isothiocyanates, derived from these glucosinolates, similarly activate TAS2R38, potentially influencing dietary preferences and intake of nutrient-rich but bitter foods.[27]Regarding non-bitter substrates, TAS2R38 exhibits low affinity for denatonium benzoate, a quaternary ammonium compound commonly used as a bitterant, with concentrations up to 1 mM failing to elicit significant activation in functional assays.[23] Potential recognition of bacterial peptides has been proposed based on broader TAS2R family interactions with microbial-derived compounds, though specific evidence for TAS2R38 remains limited. In terms of cross-reactivity, while AHLs and isothiocyanates may engage multiple TAS2Rs (e.g., TAS2R10 for certain AHL variants), TAS2R38 displays a distinctive preference for thiourea-like structures among these substrates, distinguishing it from other family members.[28][29]
Genetic Variation
Common Polymorphisms
The TAS2R38 gene features three principal missense single nucleotide polymorphisms (SNPs): rs713598 (c.145C>G, p.Pro49Ala), rs1726866 (c.785C>T, p.Ala262Val), and rs10246939 (c.886G>A, p.Val296Ile).[30] These variants occur within the coding region and exhibit high linkage disequilibrium (>0.9) across populations, primarily defining two major haplotypes: PAV (Pro49-Ala262-Val296, encoded by C-C-G alleles) and AVI (Ala49-Val262-Ile296, encoded by G-T-A alleles).[31] Rare haplotypes such as AAI and AAV arise from alternative combinations but occur at lower frequencies globally.[32]Haplotype frequencies differ markedly by ancestry. In European-descent populations, the PAV haplotype reaches approximately 50%, with the AVI haplotype also around 50%, yielding an AVI/AVI diplotype frequency of about 25%; recent large-scale analyses (e.g., from 1000 Genomes Project data as of 2025) report AVI/AVI diplotype frequencies of approximately 31% in European populations.[33][34] Asian populations show elevated AVI prevalence, for instance ~66% in Chinese cohorts, alongside reduced PAV at ~30%.[7]African populations display greater haplotype diversity, with PAV at ~40%, higher heterozygosity (PAV/AVI ~46%), and elevated rare variants like AAI (~23% in African Americans).[35][34]Standard nomenclature designates diplotypes as PAV/PAV, PAV/AVI (heterozygous), and AVI/AVI based on these SNPs.[30]Genotyping typically employs polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, which exploit allele-specific restriction sites (e.g., loss of a HaeIII site at rs713598 for the G allele), or direct DNA sequencing for confirmation.[36]
The TAS2R38 gene encodes a G protein-coupled receptor with significant functional variation driven by haplotypes defined by three key single nucleotide polymorphisms (SNPs): rs713598 (Pro49Ala), rs1726866 (Ala262Val), and rs10246939 (Val296Ile). The most common functional haplotype, PAV (Pro49-Ala262-Val296), confers high-affinity binding to bitter agonists like phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), enabling robust activation of downstream signaling pathways. In contrast, the AVI haplotype (Ala49-Val262-Ile296) represents a loss-of-function variant, exhibiting no detectable response to these ligands even at concentrations up to 1 mM, due to impaired ligand recognition and receptor activation.[21]Structural modeling reveals that the Ala262Val substitution in the AVI haplotype disrupts the ligand-binding pocket located between transmembrane helices (TM) 3 and 6, altering the geometry and reducing interactions with key residues such as Asn103, which forms a critical hydrogen bond with the N-C=S moiety of PTC. This change indirectly destabilizes the pocket by affecting hydrophobic packing and hydrogen bond networks involving Trp99 and Met100. Additionally, the Val296Ile substitution impacts TM7 stability by weakening hydrophobic interactions with Phe255 on TM6, leading to displacements exceeding 3 Å in the activation region and preventing conformational changes necessary for G protein coupling. These alterations collectively abolish agonist-induced signaling in AVI variants, as confirmed by mutagenesis studies showing near-zero maximal activity (e.g., 0.04 ΔF/F₀) compared to wild-type PAV.[37]Functional assays using heterologous expression in HEK293T cells demonstrate that PAV variants elicit strong calcium mobilization (Ca²⁺) responses to PTC (EC₅₀ ≈ 1.1 μM, ~100% activation relative to controls), while AVI variants show no Ca²⁺ flux or activation even at saturating ligand concentrations, highlighting complete loss of signaling efficiency. Heterozygous PAV/AVI diplotypes exhibit intermediate sensitivity, with approximately 50% of the PAV response amplitude and thresholds approximately 2-fold higher than in PAV homozygotes, reflecting haploinsufficiency in receptor function. Rare haplotypes such as PVI (Pro49-Val262-Ile296) and AAV (Ala49-Ala262-Val296) display partial loss-of-function, achieving only ~40% of PAV's maximal Ca²⁺ activation and reduced agonistaffinity, underscoring a spectrum of functional impairment across variants.[21]
Expression Patterns
Oral Expression
TAS2R38 is primarily expressed in type II taste receptor cells located within the fungiform and circumvallate papillae of the human tongue.[38] These cells form the core gustatory structures responsible for detecting bitter compounds in the oral cavity.[10]High levels of TAS2R38 mRNA have been detected in the human tongue epithelium, particularly in tissues encompassing fungiform and circumvallate papillae, as confirmed by RT-PCR and in situ hybridization techniques.[38] Within these taste buds, TAS2R38 is co-expressed with key signaling molecules such as gustducin (GNAT3) and phospholipase C β2 (PLC-β2), which are hallmarks of type II taste cells and facilitate the transduction of bitter signals.[18] This co-localization ensures efficient coupling of the receptor to the intracellular bitter taste signaling pathway.[10]At the cellular level, TAS2R38 protein localizes to the apical membrane of taste receptor cells, where its microvilli extend into the taste pore to interact directly with soluble bitter tastants in the oral environment.[18] This positioning enables rapid detection and response to potential toxins, allowing for quick protective reflexes such as aversion or expulsion.[39]Bitter taste perception declines in the elderly, contributing to age-related reductions in taste bud density and overall gustatory sensitivity.[40][41]
Extra-Oral Distribution
TAS2R38 is expressed in the respiratory epithelium, particularly in the ciliated cells of the upper airways and nasal sinuses, where it plays a role in innate immune defense by detecting bacterial quorum-sensing molecules such as acyl-homoserine lactones. Activation of TAS2R38 in these cells triggers an increase in intracellular calcium, leading to enhanced beat frequency of motile cilia, which facilitates mucociliary clearance of pathogens.[42]In the gastrointestinal tract, TAS2R38 is localized to enteroendocrine cells of the colonic mucosa and small intestine, where it senses bitter compounds and modulates the release of gut hormones. Notably, stimulation of TAS2R38 in these cells promotes the secretion of cholecystokinin (CCK), a gastrointestinal hormone that slows gastric emptying and nutrient absorption, potentially protecting against ingestion of toxic substances.[43][44]Beyond these primary sites, TAS2R38 exhibits expression in several other extra-oral tissues, including the thyroid gland, where it is present in thyrocytes and influences thyroid hormone production through regulation of thyroid-stimulating hormone responsiveness. In the testes, TAS2R38 mRNA levels are relatively high, though specific functional roles remain to be fully elucidated. Detectable but low levels of expression occur in the pancreas, primarily in exocrine glandular cells, while expression in the liver is minimal or undetectable.[45][46][2]Extra-oral TAS2R38 signaling generally involves G-protein-coupled pathways similar to those in taste cells, such as coupling to gustducin or other Gα subunits, but these are adapted to elicit tissue-specific responses like hormone secretion or ciliary motility rather than neural transmission.[46]
Clinical and Physiological Significance
Taste Perception Variability
Variability in bitter taste perception, particularly to compounds like phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP), is largely driven by genetic polymorphisms in the TAS2R38 gene, resulting in distinct taster phenotypes. Individuals homozygous for the functional PAV haplotype (PAV/PAV) are classified as sensitive tasters, capable of detecting PTC at low concentrations due to a fully active bitter taste receptor. In contrast, those homozygous for the non-functional AVI haplotype (AVI/AVI) are non-tasters, remaining insensitive to PTC even at high concentrations, as the receptor fails to respond effectively to these ligands. Heterozygous PAV/AVI individuals exhibit intermediate sensitivity, often categorized as medium tasters.[47]The perception of PTC and PROP shows strong heritability, estimated at approximately 70-75% from twin and family studies, indicating a substantial genetic basis for individual differences in bitter taste sensitivity. Variations in TAS2R38 account for 50-80% of the phenotypic variance in this trait, with the PAV and AVI haplotypes being the primary contributors to the bimodal distribution of taster status observed in populations. This genetic influence translates molecular differences in receptor function—where PAV enables robust activation and AVI results in loss of responsiveness—directly to sensory outcomes in humans.[48][47]Sensory testing for taster classification typically involves filter paper strips impregnated with PTC or PROP, or serial dilutions of these compounds in solution, allowing participants to report detection or intensity ratings. These methods reliably distinguish sensitive tasters, medium tasters, and non-tasters based on threshold responses, with strips providing a simple, non-invasive alternative to liquid solutions for large-scale phenotyping. Population studies reveal varying prevalence of non-tasters (AVI/AVI): approximately 25-50% among Caucasians, reflecting higher AVI allele frequencies, while rates are lower (around 10% or less) in Asian populations due to reduced AVI prevalence.[49][50]
Associations with Diet and Behavior
Variants in the TAS2R38 gene, particularly the non-functional AVI haplotype, are associated with reduced aversion to bitter-tasting foods, leading to differences in dietary preferences and intake. Individuals homozygous for the AVI haplotype (non-tasters) exhibit higher consumption of bitter vegetables such as broccoli and Brussels sprouts compared to those with the functional PAV haplotype (tasters), as they perceive less bitterness from glucosinolates in these foods. For instance, in a cohort of community-dwelling Caucasian adults, AVI/AVI individuals had 2.6 times higher odds of increased vegetable intake than PAV carriers.[51] Conversely, non-tasters show greater preference for and intake of sweet and high-fat foods, contributing to higher overall energy consumption. Studies indicate that non-tasters consume more sweet-tasting items and have elevated fat preferences, potentially due to broader acceptance of varied flavors without bitter interference.[52]The TAS2R38 genotype also influences substance use behaviors, with the AVI haplotype linked to increased risk of smoking and alcohol consumption. In European-American populations, AVI carriers are more likely to be smokers, with haplotype frequencies significantly higher among smokers (58.7% vs. 51.5% in non-smokers, p=0.002); this association holds for heavy smoking (>20 cigarettes/day). The PAV haplotype, conversely, is associated with reduced nicotine dependence and lower smoking prevalence. Similarly, AVI/AVI homozygotes report higher alcohol intake than PAV/PAV individuals, possibly due to diminished bitter perception of ethanol and related compounds.[53][54]Associations with obesity highlight metabolic implications of these variants, particularly in recent cohort studies. The AVI haplotype correlates with higher body mass index (BMI), with non-taster females showing BMI values approximately 1.7–4 kg/m² greater than tasters in Italian and young adult male cohorts, respectively. This link is attributed to increased caloric intake from preferred sweet and fatty foods among non-tasters. For example, in a 2022 study across racial groups, AVI/AVI diplotypes elevated obesity risk (OR up to 1.5 in Europeans and Asians), independent of other factors.[55][56][35]Behavioral mechanisms underlying these associations involve differential aversion learning, where tasters (PAV carriers) develop stronger conditioned aversions to bitter cues, reducing intake of potentially risky substances like alcohol and tobacco. This sensory-driven learning promotes cautious dietary choices in tasters, limiting exposure to bitter toxins, while non-tasters lack this deterrent, leading to broader but riskier consumption patterns.[57]
Role in Immunity and Disease
TAS2R38 contributes to innate immunity in the respiratory tract by detecting bacterial quorum-sensing molecules, such as acyl-homoserine lactones produced by Pseudomonas aeruginosa, which activate the receptor in airway epithelial cells. This activation triggers intracellular calcium signaling, leading to increased nitric oxide (NO) production, which enhances mucociliary clearance and directly kills bacteria, thereby reducing infection risk.[23][58] In human sinonasal epithelial cells, TAS2R38-mediated NO release has been shown to inhibit Pseudomonas growth, highlighting its role in host defense against gram-negative pathogens.[23]Individuals with the functional PAV haplotype of TAS2R38, who are bitter tasters, exhibit enhanced upper respiratory defense compared to non-tasters with the AVI haplotype. Clinical studies indicate that PAV/PAV homozygotes have a significantly lower risk of chronic rhinosinusitis, with an odds ratio of 0.44 (95% CI: 0.24–0.81) relative to AVI/AVI individuals, due to more effective pathogen clearance.[23] This genetic variation influences susceptibility to upper respiratory infections, as PAV carriers demonstrate stronger innate immune responses in the sinonasal epithelium.[42]Beyond respiratory immunity, TAS2R38 variants are associated with broader disease outcomes. The AVI haplotype reduces the odds of attaining exceptional longevity, as evidenced by lower AVI frequencies (40.42%) in centenarians compared to controls (51.10–58.16%), with significant differences in genotype distribution (χ² = 8.855, P = 0.0119).[4] In thyroid function, TAS2R38 and related bitter taste receptors detect compounds like propylthiouracil (PROP), modulating thyrocyte activity and hormone production (T3/T4); polymorphisms in TAS2R38 influence sensitivity to such agonists, potentially affecting thyroid regulation.[59] Studies from 2020–2023 have explored links to COVID-19 severity, suggesting that TAS2R38 variations may modulate innate immune responses to SARS-CoV-2, though results are inconsistent across cohorts.[60][61]Therapeutically, TAS2R38 agonists, such as denatonium benzoate or bacterial-derived quinolones, hold promise for treating chronic respiratory diseases by boosting mucociliary clearance and NO-mediated antimicrobial activity. In patients with primary ciliary dyskinesia or chronic rhinosinusitis, activating TAS2R38 could enhance airway defenses, with preclinical models showing improved bacterial killing and reduced inflammation.[42][62]