The structure and function of taste G protein-coupled receptors and their implications in diseases

Abstract

Taste G protein-coupled receptors (GPCRs), including sweet (TAS1Rs) and bitter (TAS2Rs) taste receptors, are essential for detecting nutrients and avoiding toxins, influencing dietary behavior, metabolism, and overall health. Beyond their role in taste perception, these receptors are widely expressed in extra-gustatory tissues, including the respiratory and gastrointestinal systems, where they regulate innate immune responses, hormone secretion, and energy balance. Dysfunctions or polymorphisms in TAS1Rs and TAS2Rs have been linked to various diseases such as asthma, type 2 diabetes, obesity, dental caries, periodontitis, and certain cancers. The structural features of these receptors, including their ligand-binding domains and signaling pathways, are central to their diverse functions. Recent studies also highlight their potential as therapeutic targets for managing conditions like metabolic syndrome and immune-related disorders. This review provides a detailed examination of the structural and functional dynamics of TAS1Rs and TAS2Rs, emphasizing their roles in disease mechanisms and exploring therapeutic strategies. While challenges remain in structural resolution and functional characterization, advancements in molecular modeling and pharmacological approaches shed light on their clinical potential. Understanding the tissue-specific roles and molecular mechanisms of taste GPCRs can pave the way for innovative treatments targeting these receptors, offering significant promise in addressing a range of health conditions.

Introduction

Taste is a vital sensory function for human beings, and it plays a crucial role in determining dietary choices. It refers to the sensation elicited by taste receptors in taste buds upon receiving external stimuli, which subsequently generate taste signals and transmit them to the central nervous system. The taste system plays a crucial role in mammals’ ability to identify nutrient-rich foods for ingestion while avoiding potentially toxic or harmful substances, thereby holding significant importance for human beings and other mammalian species.^1,2 Mammals primarily perceive tastes as sweet, bitter, sour, salty, and umami. Generally speaking, sweetness indicates energy-dense foods, umami aids in amino acid absorption, saltiness helps maintain electrolyte balance in daily diets, and sourness often signifies excessive acidity or food spoilage. Natural bitterness is commonly linked to the defense mechanisms against predation of animals and plants, whereas bacterial quorum-sensing molecules activating bitter taste receptors may contribute to bitterness in certain spoiled foods.

The first taste receptor gene TAS1R1 was discovered in 1999 by Hoon et al.³ when they sequenced the cDNA library of taste cells on the tongue of mice. Subsequently, the TAS1R2 gene was identified based on the TAS1R1 gene.³ In 2001, researchers identified TAS1R3, a gene related to the perception of sweet taste, on human chromosome 4, thus identifying the first potential sweet taste receptor.^4,5,6,7,8,9 Currently, research on bitter, sweet and umami taste receptors in mammals is relatively well-established. Sweet, bitter, and umami perception are mediated by G-protein-coupled receptors (GPCRs) and their downstream second messenger signaling pathways, while salty or sour recognition mainly relies on ion channels. GPCRs are crucial proteins involved in cell signaling. The taste GPCRs can be categorized into two major families: type 1 taste receptors (TAS1Rs) and type 2 taste receptors (TAS2Rs). The sweet and umami taste receptors (TAS1Rs) belong to class C GPCRs and form heterodimers consisting of an extracellular domain and a seven transmembrane domain (7TM).³ On the other hand, bitter taste receptors (TAS2Rs) are generally classified as class A (rhodopsin-like) GPCRs.³ However, this assignment remains debated because TAS2Rs share limited sequence similarity with any other GPCR class, and some researchers supported that they should be classified separately as class T.¹⁰ In the phylogeny-based GRAFS framework proposed by Fredriksson and Schiöth, TAS2Rs were grouped with Frizzled receptors as a separate family (F).¹¹ Therefore, the precise phylogenetic position of TAS2Rs remains ambiguous and requires further investigation. Despite their structural diversity, signaling from both TAS1Rs and TAS2Rs converges on downstream effectors including PLCβ2 and TRPM4/5.^12,13

Taste GPCRs are not limited to the tongue (taste buds) but are also expressed in various tissues throughout the body, where they perform diverse physiological functions. For instance, TAS2Rs have been found in the respiratory system,^14,15,16 gastrointestinal tract,¹⁷ urogenital tract,^18,19 and periodontal tissues,^20,21 suggesting a role in detecting harmful substances and regulating immune responses in these areas. TAS1Rs are expressed in the gastrointestinal tract, including the small and large intestines, where they likely participate in the regulation of nutrient absorption and hormone secretion.^22,23 In the cardiovascular system, TAS2Rs are present in vascular smooth muscle and heart tissues, where they influence blood pressure regulation and cardiac function.²⁴ Additionally, taste GPCRs in the brain and nervous system play roles in neurotransmission and the regulation of excitability and responsiveness.^25,26 Thus, the widespread distribution of taste receptors throughout various tissues highlights their involvement in processes beyond traditional taste perception, such as immune regulation, endocrine signaling, and tissue responses to external stimuli.

The dysfunction of taste GPCRs may have implications for both health and disease. On the one hand, taste GPCRs in taste buds generate peripheral taste signals and contribute to taste perception, which inevitably affects human health by affecting food intake and diet choice. In extra-gustatory locations, taste GPCRs are expressed in a variety of cell types, including solitary chemosensory cells (SCCs)/tuft cells, fibroblasts, enteroendocrine cells, pancreatic β cells, immune cells, etc. These “ectopic” taste GPCRs contributes to various physiological functions, including innate immune regulation, hormone and metabolism regulation, and are intricately linked to the occurrence and progression of numerous diseases, thereby rendering them potential therapeutic targets.^27,28 The in-depth investigation into the functional mechanism of taste GPCRs beyond the realm of taste perception and the experimental structural analysis of taste GPCRs serve as crucial prerequisites for comprehending the involvement of taste GPCRs in diseases and facilitating the development of efficacious pharmaceuticals, which constitute focal points within this review. Moreover, the scope of this review will be restricted to the sweet and bitter taste GPCRs, as there exists a plethora of comprehensive studies available on these two types of taste GPCRs in various diseases.

Signaling and structures of sweet and bitter taste GPCRs

Distribution of sweet and bitter taste signaling

While taste perception is limited to the sensory cells in the taste buds, taste receptors are also expressed and functional in various extra-gustatory tissues, where their signaling pathways differ.²⁹ Although mediated by different GPCRs, sweet and bitter taste signaling share a prevalent pathway in taste buds (Fig. 1).³⁰ Binding of tastants to sweet or bitter taste GPCRs activates the heterotrimeric G protein α-gustducin, leading to release of the β3γ13 subunit that activates phospholipase C-β2 (PLCβ2).^31,32 PLCβ2 hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3), which binds to IP3 receptor type 3 (IP3R3) on endoplasmic reticulum, causing Ca²⁺ release.^33,34 The increase in intracellular Ca²⁺ opens transient receptor potential channel M5 (TRPM5) and TRPM4 channels, resulting in Na⁺ influx that depolarizes the cell.¹³ In the scenario of taste perception, ATP is released by taste cells via voltage-gated channels CALHM1/CALHM3 in response to action potentials, serving as the primary neurotransmitter.^35,36 This release stimulates purinergic receptors 2 and 3 (P2X2 and P2X3) on afferent cranial nerves, thereby activating the gustatory cortex.³⁷ In addition to the above signaling pathway, sweet and bitter taste signaling is also regulated by cyclic adenosine monophosphate (cAMP).³⁸ Early electrophysiological studies demonstrated that the application of cAMP analogs induces depolarization of taste bud cells by reducing K⁺ efflux through Protein Kinase A (PKA)-mediated phosphorylation of K⁺ channels.³⁹ Both rat and hamster studies show that saccharin or sucrose depolarizes taste bud cells and elicits action potentials, and a permeable analog of cAMP can mimic this effect.^40,41 Therefore, the cAMP–AC–PKA pathway may regulate sweet taste transduction in taste buds, although current evidence remains insufficient. Unlike sweet taste GPCRs, bitter stimuli cause the dissociation of Gα-gustducin, a transducin-family G protein that participates in taste signaling, including umami perception.^42,43 The dissociated Gα-gustducin activates phosphodiesterase (PDE), leading to reduced intracellular cAMP levels and downstream modulation of PKA activity.⁴⁴ Biochemical and rapid kinetic studies showed millisecond-scale reductions in cAMP in response to bitter tastants that were abolished by Gα-gustducin–specific antibodies but unaffected by inhibition of PLCβ2, demonstrating a Gα-gustducin–dependent regulation of cAMP levels.⁴⁵ The reduction in cAMP levels affected PKA activity, thereby relieving inhibition of the PLCβ2-IP3 signaling pathway. Consequently, reduced PKA-mediated phosphorylation promotes the release of stored Ca²⁺ and neurotransmitters, thereby amplifying the bitter taste signal.⁴⁶ Beyond stimulus-evoked regulation, basal regulation of cAMP-mediated signaling also appears to be important for maintaining taste cell responsiveness. Clapp et al. found that basal cAMP levels are elevated in taste buds from Gα-gustducin–deficient mice and that pharmacological inhibition of PKA restores Ca²⁺ responses to bitter stimuli.⁴⁷ Based on these observations, they proposed a model in which Gα-gustducin is tonically active at rest, maintaining the low cAMP levels to ensure the key Ca²⁺ signaling effectors (PLCβ2 and IP₃R3) remain competent to trigger a Ca²⁺ response.⁴⁷

Fig. 1

Shared signaling pathway of sweet and bitter taste GPCRs. Left, Sweet taste GPCRs (TAS1R2/TAS1R3); Right, Bitter taste GPCRs (TAS2Rs). Sweet or bitter ligand binding to TAS1R2/TAS1R3 or TAS2Rs activates the taste G-protein gustducin (Gα/β/γ), which stimulates PLCβ2 to hydrolyze PIP2 into IP3 and DAG. IP3 gates IP3 receptors (IP3R) on the endoplasmic reticulum, leading to Ca²⁺ release and TRPM4/5 activation, which causes depolarization and action potential generation. Voltage-gated channels CALHM1/CALHM3 respond to action potentials and release adenosine-5’-triphosphate (ATP), serving as the primary neurotransmitter

The signaling components and pathways in extra-gustatory tissues partially overlap with the classic taste transduction cascade in taste buds. For example, in intestinal tuft cells, activation of TAS2Rs leads to dissociation of Gα-gustducin/Gβ1γ13 and/or Gαo/Gβ1γ13, where Gβ1γ13 engages a PLCβ2–IP3 pathway similar to that in taste buds. IP3 binds to and activates IP3R2, instead of IP3R3 found in taste buds, which exhibits a higher affinity for IP3 but a lower sensitivity to Ca²⁺. The release of Ca²⁺ activates TRPM5 only, causing Na⁺ influx and membrane depolarization, which ultimately promoting the release of IL-25 and triggering type 2 immune responses.⁴⁸ However, the signal transduction pathways differ across various extra-gustatory tissues. In cystic fibrosis airway epithelial cells, upregulated Gαi suppresses AC activity and lowers intracellular cAMP levels, which in turn enhances Ca²⁺ signaling and TAS2R14-mediated innate immune responses.⁴⁹ Moreover, TAS2Rs induce airway smooth muscle relaxation through four potential mechanisms, and the underlying signaling pathways are distinct.^50,51,52,53 Therefore, the signaling components and pathways of sweet and bitter taste GPCRs in extra-gustatory tissues may depend on cell type and functional context, yet the precise mechanisms governing these pathways remain incompletely understood.

Protein structure of TAS1R2/TAS1R3

The Class C GPCR family is known for its unique domain composition and functional characteristics, primarily regulating physiological functions by binding to external chemical signals like neurotransmitters or metabolites. TAS1R2 and TAS1R3 detect sweet taste molecules through heterodimer formation, sharing three major domains: (1) the large extracellular Venus Flytrap Domain (VFT) responsible for initial ligand binding. (2) the Cysteine-Rich Domain (CRD) connecting VFT and transmembrane domain, facilitating signal transduction. (3) the classical seven-fold Transmembrane Domain (TMD), activating G-proteins and downstream signaling pathways.⁵⁴ Other members of Class C GPCRs, such as metabotropic glutamate receptor (mGluR) and calcium-sensing receptor (CaSR), also possess the VFT, CRD, and TMD structure, serving as important references in studying sweet taste receptor structure.

Sweet taste ligands and their binding sites

The TAS1R2/TAS1R3 heterodimers exhibit the ability to bind various types of ligands, including small-molecule sweeteners, protein sweeteners, and allosteric regulatory molecules.^55,56,57 Each type of ligand interacts with a specific binding site to initiate or modulate sweet taste signaling (Supplementary Table. 1). It has been demonstrated that small-molecule sweeteners, such as saccharides, primarily activate the receptor by binding to the VFT domain of TAS1R2. The VFT domain of TAS1R2 captures these molecules through two “splint-like” structures, leading to conformational changes and subsequent activation of downstream signaling cascades.⁵⁷ These small-molecule sweeteners perfectly fit into the binding site of TAS1R2 due to their smaller size and simpler structure. For instance, sucrose, a natural carbohydrate, binds to the VFT region of both TAS1R2 and TAS1R3 with an EC₅₀ value of 62 mmol/L.⁵⁵ As peptide-based small molecule sweeteners, aspartame and neotame predominantly bind to the VFT region of TAS1R2 with EC₅₀ values of 0.75 mmol/L and 5 mmol/L respectively.^55,58 Saccharin and Acesulfame K are sulfonamide-based sweeteners that also interact with the VFT region of TAS1R2 at EC₅₀ values of 0.19 mmol/L and 0.54 mmol/L respectively.^55,58 In addition to VFT-targeting sweeteners, some small-molecule sweeteners have been reported to bind to the TMD of TAS1R2/TAS1R3, including cyclamate and perillartine. For instance, cyclamate functions as a partial agonist with species-dependent activation, binding to human TAS1R3 within a pocket formed by transmembrane helices 3, 5, and 6, as well as extracellular loop 2. This interaction induces a conformational shift in the helical bundle, facilitating G protein coupling and triggering a sweet taste response.^59,60 Similarly, perillartine activates the receptor through direct interaction with the TMD of TAS1R2, bypassing the need for VFT engagement and modulating sweet taste in a species-specific manner.^61,62

In contrast, protein-based sweeteners such as thaumatin typically bind to the VFT domain of TAS1R3 due to their substantial molecular weight. The VFT domain of TAS1R3 is relatively large and flexible, allowing it to accommodate these macromolecular ligands effectively. Existing literature suggests that the binding of protein-based sweeteners to TAS1R3 necessitates higher specificity, as they must interact with more intricate binding pockets in order to initiate signaling.⁶³ These protein molecules provide a stronger activation signal by selectively binding to specific regions of TAS1R3, thereby enhancing the perception of sweetness. Protein sweeteners like thaumatin and monellin exhibit exceptionally high sweetness perception efficiency and target either the CRD or VFT region of TAS1R3 with very low EC₅₀ values (0.005 mmol/L and 0.001 mmol/L respectively).⁶⁴ The binding sites between these protein molecules and TAS1R3 are highly specific, resulting in intense and long-lasting perception of sweetness.

Allosteric modulators regulate the conformational transitions of the TAS1R2/TAS1R3 heterodimer, altering the intensity of sweet taste signal transmission, and can be categorized into sweet taste enhancers and inhibitors. Sweet taste enhancers primarily bind VFT domain of TAS1R2, stabilizing its active conformation. This enhances the affinity of sweet substances, such as sucrose or aspartame, reduces their EC₅₀ values, and amplifies the sweet taste signal.⁶⁵ Additionally, sweet taste enhancers interact with key residues in the VFT domain (e.g., K65, Y103, and D307), lowering the energy required for conformational closure, thereby increasing the sensitivity of the receptor and enhancing sweet perception. In contrast, sweet taste inhibitors, such as lactisole, typically act on the TMD of TAS1R3. By interacting with specific residues (e.g., A733 and R790), these inhibitors induce an inactive receptor conformation, thereby blocking signal transmission and suppressing sweet perception.⁵⁷

Structure of human TAS1R2/TAS1R3

The structural resolution of TAS1R2/TAS1R3 faces several technical challenges, including low heterologous expression, the impact of receptor modification on stability, and difficulty in vitro extraction. These issues significantly limit detailed structural investigations of TAS1R2/TAS1R3 heterodimers, especially obtaining high-resolution crystal structures. Low heterologous expression is a major bottleneck for TAS1Rs research as it often results in insufficient protein production under laboratory conditions, making it difficult to obtain functional proteins for subsequent analysis.^66,67 GPCRs require specific cellular environments and cofactors to maintain their native conformation and activity when expressed in heterologous systems, further complicating the expression and purification processes for TAS1Rs.⁶⁸ Post-translational modifications like glycosylation or phosphorylation significantly influence the conformation and functionality of TAS1R2 and TAS1R3 receptors.⁶⁹ Glycosylation not only aids proper protein folding and stability but also affects membrane localization and ligand binding ability.⁶⁹ However, these modifications pose challenges in maintaining the active structure of the receptor during in vitro analysis. Additionally, modeling modifications such as phosphorylation that occur under specific cell signaling conditions prove challenging in vitro systems, limiting comprehensive investigation into receptor function. The complex structures of TAS1R2/TAS1R3 heterodimers make them prone to disassembly or loss of activity during extraction. Detergent treatment poses a significant risk to the transmembrane regions of GPCRs by potentially causing non-functional aggregation or structural disintegration.⁷⁰ Furthermore, as the active structure of the TAS1Rs relies on cooperation with other molecules or cofactors, extracting the receptor alone may result in the loss of these crucial accessory components, further complicating efforts to obtain a complete and functional structure.⁶⁸

In 2025, three landmark studies have been published successively, deconstructing the structure of the sweet taste receptors TAS1R2/TAS1R3 for the first time. Zuker’s research team engineered an innovative dual-promoter baculoviral construct to co-express both subunits, successfully obtaining stable heterodimer formation while avoiding nonfunctional TAS1R2 homodimers during purification.⁷¹ Using single-particle cryo-EM, they characterized the agonist-bound TAS1R2/TAS1R3 heterodimers, including sucralose and aspartame. Consistent with predictions, sweet ligands bound exclusively to the VFT domain of TAS1R2 while TAS1R3 remained open and ligand-free, confirming the asymmetric architecture of the heterodimer. Mutation analysis identified key residues in the TAS1R2 binding pocket that govern ligand specificity and potency, linking structural contacts to functional activation. Beyond ligand recognition, the study traced conformational changes across domains: agonist-induced closure of the TAS1R2 VFT was transmitted through the CR linkers, where a notable kink in the TAS1R3 linker intercalated into the VFT dimer interface. This arrangement likely couples ligand binding to TMD rearrangements, creating a TM6–TM6 interface favorable for G protein engagement and intracellular signaling. Functionally, TAS1R2 emerges as the principal ligand-binding and G-protein-coupling subunit, whereas TAS1R3 contributes critical allosteric and structural roles at the VFT–CR interface and within the TMD dimer. Regrettably, the absence of the apo structure of the receptor restricted the characterization of structural differences between the inactive and active states of the heteromeric receptor. Nevertheless, this study established a structural and mechanistic framework that was supported by the subsequent two researchers.

Subsequently, Shi et al. resolved the human sweet taste receptor TAS1R2/TAS1R3 in both apo and sucralose-bound states using high-resolution cryo-EM, thereby addressing limitations of the Zuker team’s work.⁷² To achieve this, they employed an innovative fluorescent-protein fusion strategy that stabilized the full-length heterodimer, once again confirming its asymmetric structure. While reaffirming the ligand specificity of the TAS1R2 VFT, the study showed that ligand binding initiates a coordinated yet modest activation cascade. Upward movement of the TAS1R2 LB2 transmits force into the CRD, bending it and shifting the VFTs, while a TAS1R3 loop is displaced in the same direction. Together, these adjustments shorten the receptor’s vertical height and propagate subtle conformational changes into the TMD. At the TMD dimer interface, activation involves only minor TM6 rotations, primarily localized to the intracellular face of TAS1R2, consistent with the observations of Zuker et al. They also emphasized that TAS1R2/TAS1R3 transduces signals through small, asymmetric conformational changes, which are distinct from the large-scale rearrangements observed in other class C GPCRs.

Recently, Wang et al. further extended these findings through cryo-EM structures of apo and sweetener-bound receptors using both human/human and human/mouse heterodimers.⁷³ This study determined the binding modes of sucralose and advantame in the TAS1R2 VFT pocket, thereby providing structural insights into receptor activation by natural sweet compounds and amino acid–based sweeteners. In addition, the authors captured two key events during activation that had not been reported previously. First, agonist binding induces clamshell closure in TAS1R2, accompanied by a stabilizing salt bridge that defines the compact state. Second, a previously undefined loose conformation was identified, in which the receptor adopts a more open, activation-prone state. This transition is driven by insertion of a TAS1R2 loop into the inter-subunit interface, displacing TAS1R3 and triggering separation of the VFT lower lobes. Notably, the TAS1R3 VFT clamshell also opens further in the loose state compared to the apo conformation. Together, these findings provide novel insights distinct from the previous two studies and suggest structure-guided strategies for designing receptor modulators, as sweeteners that stabilize the loose state may enhance perceived sweetness.

Protein structure of TAS2Rs

In humans, 26 TAS2Rs have been identified, while only the structures of TAS2R14 and TAS2R46 are determined.⁷⁴ Notably, structural comparisons between these two receptors reveal substantial differences, particularly in the extracellular regions, suggesting that structural features identified in one TAS2R may not be generalizable across the family.⁷⁵ This structural heterogeneity likely underlies the distinct ligand recognition profiles of individual TAS2Rs and may contribute to their tissue-specific expression patterns. Functionally, TAS2Rs are activated by an exceptionally broad spectrum of bitter ligands, including natural compounds (e.g., alkaloids, terpenoids, flavonoids), synthetic chemicals, toxic plant metabolites, and many clinically used drugs. This diversity reflects both the evolutionary role of TAS2Rs in detecting harmful substances and their emerging pharmacological relevance. BitterDB, a comprehensive resource for bitter-tasting molecules and their associated receptors, currently catalogs over 2 200 bitter compounds across 66 species and includes approximately 700 ligands with defined TAS2R associations (as of 2025).⁷⁶ Given its depth and accessibility, detailed discussion of bitter ligands is omitted here.

Early structural studies of bitter taste GPCRs were mainly conducted through homology modeling, ligand docking experiments, and functional heterologous expression combined with in vitro mutagenesis.⁷⁷ Brockhoff et al. apply point mutagenesis and function assay to identify key residues involved in ligand binding of TAS2R46. This strategy also enabled iterative refinement of the obtained structural models.⁷⁸ Subsequently, Nowak et al. demonstrated that numerous mutations enhanced the potency and/or efficacy of specific agonists by generating point mutants of TAS2R14, revealing its broad ability to recognize diverse agonists.⁷⁹ In addition to these studies, a series of early mutational analyses from the Chelikani laboratory provided functional insights into bitter taste receptor activation and regulation at a time when high-resolution structural information was not yet available.^80,81,82,83 These studies proposed that interhelical and intracellular interaction networks stabilize TAS2Rs in an inactive conformation.^80,82 Functional mutagenesis further showed that disruption of these interactions by selected point mutations can lead to constitutive receptor activity, manifested as detectable signaling output in the absence of ligand.^80,81,82 Notably, mutations within the TM5–ICL3–TM6 region were found to be particularly prone to inducing constitutive activity, suggesting that these residues may impose conformational constraints on TM6 and raise the energetic barrier for activation.⁸² In addition, early mutational studies indicated an association between membrane cholesterol levels and the signaling strength of TAS2Rs.⁸³ However, these predictions have significant limitations due to the low sequence homology with other GPCR families and the difficulty in obtaining experimental structures. In recent years, high-resolution structures of TAS2R46 and TAS2R14 have provided new insights for subsequent studies.^{84,85,86,87,88}

The TAS2R46 receptor is widely acknowledged as a broad-spectrum bitter taste receptor with the ability to recognize various ligands (Supplementary Table. 1).⁸⁴ Its structural analysis provides crucial insights into this characteristic.⁸⁹ The ligand-binding pocket of TAS2R46 is described as relatively deep and exhibits significant structural flexibility, enabling it to accommodate and identify bitter molecules with diverse chemical properties. In the investigation of its cryo-EM structure, multiple polar and non-polar amino acid residues were observed surrounding the binding pocket of TAS2R46. These residues form stable interactions with ligand molecules through hydrogen bonding, van der Waals forces, and hydrophobic interactions.⁸⁹ This diversity in binding modes greatly expands the range of ligand recognition for TAS2R46, allowing it to interact with bitter molecules of varying sizes, shapes, and chemical properties. To be specific, strychnine interacts with conserved amino acids within the TAS2R46 binding pocket through hydrogen bonding and hydrophobic interactions.⁸⁹ These interactions induce rearrangements in the transmembrane helices, particularly helices 6 and 7, creating an optimal conformation for downstream G protein signaling.⁸⁹ Functional analyses indicate that TAS2R46 primarily engages G_i/o-type G proteins, activating intracellular signaling pathways that regulate calcium ion release and trigger bitter taste signaling.⁸⁹

The recent studies on TAS2R14 provide crucial insights into its structure, ligand binding, and signal transduction (Supplementary Table 1).^85,86,87,88 TAS2R14 displays two distinct pockets, a conventional orthosteric binding site and a unique intracellular allosteric site, which are connected by an elongated cavity.⁸⁵ Notably, Hu et al. reported that aristolochic acid (AA) bound to a third binding pocket of the TAS2R14-miniG_s/gust complex, which is situated beneath pocket 2.⁸⁶ Cholesterol occupies the orthosteric site, engaging in hydrophobic interactions with key residues like W89^3.32, critical for stabilizing receptor conformation. An intracellular binding site is targeted by ligands like compound 28.1 (Cpd 28.1) and flufenamic acid (FFA), forming interactions that enhance activation stability. Interestingly, cpd 28.1 was found at both intracellular and extracellular binding sites and to form more pronounced hydrophilic interactions with the orthosteric site than cholesterol.⁸⁷ According to Peri et al., the detected cholesterol may result from hydrolysis of the excess cholesteryl hemisuccinate (CHS) used during protein purification, as their structural characterization using lower CHS concentrations indicated FFA binding at the orthosteric site as well.⁸⁸ Upon ligand binding, conformational changes are observed in transmembrane helices, especially TM6, facilitating G-protein coupling. Cpd 28.1 and FFA act as both a direct agonist and a positive allosteric modulator, stabilizing the receptor’s active state and promoting interactions with G_α-gustducin and G_i1.⁸⁸ This dual binding mechanism underscores the broad ligand recognition ability of TAS2R14 and its ability to signal via multiple pathways.

Collectively, these cryo-EM studies provide a structural basis for the functional hypotheses proposed by earlier mutational analyses of bitter taste GPCRs.^{84,85,86,87,88} The extensive networks of polar and hydrophobic interactions observed in TAS2R14 and TAS2R46 are compatible with the conformational restraint mechanisms proposed by the Chelikani laboratory.^{84,85,86,87,88} Moreover, the direct visualization of TM6 outward movement and formation of the intracellular G-protein–binding cavity highlights TM6 rearrangement as a common activation feature of bitter taste GPCRs.⁸⁴ Notably, the identification of a cholesterol-binding pocket in TAS2R14 provides a structural rationale for earlier observations that membrane cholesterol modulates bitter taste receptor signaling.^85,86,87 Thus, despite being derived from different TAS2R subtypes, the functional conclusions of early mutational studies are broadly supported by current structural evidence.

In-depth analysis of the amino acid sequences of TAS2R46 and TAS2R14 allowed identification of crucial residues that are closely related to ligand binding. These residues play a pivotal role in facilitating the ligand binding process and are often conserved amino acids responsible for establishing stable interactions with specific chemical groups. Unveiling the precise location and nature of these critical residues is beneficial for comprehending the specific ligand recognition mechanisms of TAS2Rs. Currently, several studies have reached a general consensus regarding the key residues of TAS2R14 binding sites.^85,86,87,88 The orthosteric pocket is formed by an extensive network of hydrophobic residues, to which cholesterol,^85,86 cpd28.1,⁸⁷ and FFA⁸⁸ can all bind. Notably, the highly conserved amino acid residue W89^3.32 forms CH-π interactions with the steroid nucleus of cholesterol, which is similar to the role of W88^3.32 in the activation of TAS2R46 by strychnine.^85,86,89 Compared to cholesterol, cpd28.1 and FFA also interact with S65^2.60 and S176^ECL2, whose critical role in receptor function has been confirmed through mutagenesis experiments.^87,88 The allosteric binding site is formed by TM3, TM5–TM7, and the cytoplasmic end of the G protein α5 helix. S194^5.54 and H276^7.49 in this site form hydrogen bonds with several agonists, and mutations in these residues reduce or eliminate their potency and efficacy of cpd28.1,^85,86,87 FFA,⁸⁸ and AA.⁸⁷ Additionally, L353^H5.25 of Gαi1 and Gα-gust interact with the fluorine of cpd28.1 and Y107^3.50 in TAS2R14, suggesting their potential role in enhancing the stability of the TAS2R14–G protein complex.^85,86,87 Unlike TAS2R14, TAS2R46 has only one extracellular orthosteric binding site, where the horizontally placed indole ring of W88^3.32 serves as a landing platform for the strychnine molecule, establishing a π-π interaction with the benzene ring of strychnine.⁷³ Kim et al. attempted to explore the intracellular binding site of TAS2R46 through structural superposition.⁸⁵ Unfortunately, despite several conserved residues in both TAS2R46 and TAS2R14, there are still notable structural differences between them. The key residues of TAS2R14 undergo flipping, displacement, and replacement at the corresponding positions in TAS2R46.⁸⁵ In summary, except for W^3.32, the specific residues involved in the ligand-binding pockets of the two receptors are variable, suggesting that bitter taste GPCRs exhibit highly diversified binding modes for agonists.

Although the presence of cholesterol in the orthosteric pocket remains debated, the observation of cpd28.1 and FFA occupying this site suggests that dual-site binding in TAS2R14 is unlikely to be incidental.^85,86,87,88 The cryo-EM structures of TAS2R14 consistently show stable conformations in which both binding pockets are occupied, suggesting that ligand binding contributes to receptor stability and activity. The ability of the orthosteric and allosteric sites to bind either identical or distinct ligands may enhance the responsiveness of TAS2R14 across varying environmental contexts and ligand concentrations, although this hypothesis requires further validation.⁷⁵ The hydrophobic, elongated tunnel connecting two pockets resembles the lipid membrane-entry pathway described in lipid GPCRs.^90,91 Kim et al. cautiously suggested that this tunnel might participate in cholesterol engagement, given the high concentration of cholesterol in the plasma membrane.⁸⁵ Notably, cpd28.1, FFA, and AA all share the general features of small bitter tastants with hydrophobic aromatic scaffolds, which may facilitate membrane diffusion and promote access to the intracellular pocket.^92,93 In contrast, the cryo-EM structure of TAS2R46 reveal a more defined ligand recognition pattern centered on residues W88^3.32 and E265^7.3984. Many clinical drugs containing an aromatic moiety and a positively charged nitrogen interact with the two key residues through π–π stacking and salt-bridge formation.⁹⁴ While, bitter tastants with a lactone substructure rely on hydrogen bonding between their carbonyl and hydroxyl groups and these residues.⁹⁵ These structural studies on TAS2R14 and TAS2R46 provide frameworks for understanding the broad spectrum of bitter taste GPCRs and offer insights into how ligands from different origins adopt distinct binding modes.

The role of sweet and bitter taste GPCRs in diseases

The physiological functions of sweet and bitter taste GPCRs vary across different tissues and cell types (Fig. 2). The upstream signals and downstream functions of taste receptors are relatively clear in certain organs, tissues, and cell types. In some studies, researchers have discovered that specific cell types within particular tissues can express taste receptors. Their functions are often investigated through in vitro experiments involving exogenous ligand addition. However, the sources of endogenous stimulation for these taste receptors within the body remain unclear, thus, the physiological roles of taste receptors in these cells remain largely unknown. Currently, it is increasingly evident that based on their expression location and classification according to upstream stimulation patterns, sweet and bitter taste receptor functionalities primarily involve aspects such as taste perception, innate immunity, and metabolic regulation. Meanwhile, taste receptors may influence other conditions such as asthma, reproductive dysfunction, and cancers through additional mechanisms, however, further research is required to substantiate these claims (Supplementary Table 2).

Fig. 2

Distribution and expression of sweet and bitter taste GPCRs in diseases. The expression of sweet and bitter taste GPCRs in different body parts is related to various pathological conditions, including oral diseases (periodontitis, dental caries), respiratory diseases (CRS, asthma), metabolic disorders (T2D, obesity), urinary diseases (urinary tract infection), reproductive conditions (PTB, male infertility), neurological disorders (AD, PD), and various cancers. Specific receptor subtypes associated with each disease are indicated

Oral diseases

Dental caries

The primary cause of dental caries is the demineralization of tooth hard tissue resulting from acid production by oral microorganisms. Diet plays a significant role in the pathogenesis of dental caries by influencing the metabolic activities of oral microorganisms. Sweet and bitter taste GPCRs can exert an influence on dietary choices, modulate the host’s innate immune response, and impact the development of caries.

Single nucleotide polymorphisms (SNPs) in the genes encoding sweet taste GPCRs have been shown to alter sweet taste preference and sugar intake, thus affecting the risk of caries.^96,97 Most studies reached the conclusion that individuals who hold an Ile191Val polymorphism in TAS1R2 consume fewer sugars and are at a lower risk of developing dental caries, while Ile homozygotes, whose carbohydrate intake is higher, showed more frequent high-risk caries experience.^97,98,99,100 However, one study reported an opposing finding: children who carried the Val allele were more frequently affected by caries than those who carried the common Ile allele.¹⁰¹ Two SNP loci of TAS1R3 (rs307355 and rs35744813) have been reported to be associated with sweet taste sensitivity,¹⁰² and the rs307355 polymorphism has been claimed as an independent risk factor for dental caries.⁹⁷ SNP rs307355 is located within the E-box transcription factor binding sites upstream of the TAS1R3 promoter, and the nucleotide variation at this site affects TAS1R3 expression by reducing promoter activity.¹⁰² In interpreting these findings, it is crucial to comprehend that the impact of taste receptor SNPs on diet and caries susceptibility is influenced by various factors such as ethnicity, age, and culture. Conversely, the correlation between taste receptor function and dental caries is evidently not fully elucidated by taste perception and dietary preference. A typical example is the finding regarding the TAS2R38 SNP and caries susceptibility.^103,104

The function of TAS2R14 and TAS2R38 in gingival epithelial cells may be associated with the innate immune response triggered by cariogenic oral bacteria Streptococcus mutans, thereby impacting the host’s susceptibility to dental caries. An in vitro study was conducted to isolate and culture human gingival epithelial cells expressing different genotypes of TAS2R38.¹⁰⁵ The results showed that TAS2R38 expression was significantly upregulated in PAV homozygous cells after S. mutans exposure, while no change was observed in AVI homozygous cells.¹⁰⁵ The secretion of IL-1α and antibacterial peptide hBD-2 in gingival epithelial cells were also affected by exposure to S. mutans and/or TAS2R38 genotype.¹⁰⁵ Although the evidence from this in vitro study is weak, some experimental results are difficult to explain, the results still suggest that TAS2R38 function in gingival epithelial cells may be involved in regulating the interaction between cariogenic bacteria and host innate immunity. Another study revealed that the quorum sensing molecule CSP-1 of S. mutans was capable of triggering the innate immune response in gingival epithelial cells through TAS2R14.¹⁰⁶ TAS2R14 facilitated intracellular calcium influx and the secretion of pro-inflammatory cytokines (IL-8) upon stimulation by CSP-1 and attracted differentiated HL-60 immune cells.¹⁰⁶ Intriguingly, treatment of gingival epithelial cells with CSP-1 inhibits the growth of Staphylococcus aureus through TAS2R14, by inducing hBD-2 secretion.¹⁰⁶ This implies that S. mutans may exploit the bactericidal effect facilitated by bitter taste receptors to secure a competitive edge within the oral biofilm, representing one of the mechanisms through which S. mutans induces dental caries. Currently, only a limited number of in vitro cell-based studies suggest that bitter receptors can influence dental caries risk through innate immune regulation. More in-depth mechanistic exploration and animal experiments are necessary to obtain reliable conclusions.

Periodontitis

The initiation of periodontitis is associated with the dysbiosis of oral microecology caused by abnormal interaction between oral microflora and the host. Gingival SCCs, a cell type expressing bitter taste receptors and taste signal transduction elements, had been identified in the gingival epithelium of mice.¹⁰⁷ Tas2r105 in gingival SCCs could be activated by gram-negative bacteria quorum sensing acyl-homoserine lactone (AHL) molecules. In mice lacking gingival SCCs (Pou2f3^−/−) or taste signal transduction molecule (Gnat3^−/−), there were disorders in secretion antimicrobial peptides (such as beta-defensin 3) in periodontal tissue, dysbiosis in periodontal microflora characterized by increased bacterial load, decreased diversity and increased pathogen NI1060, ultimately leading to more severe inflammation and alveolar bone resorption in a periodontitis model.¹⁰⁷ These findings demonstrate that gingival SCCs act as immune sentinels in the periodontium, recognizing bacterial metabolites through bitter taste receptors and mediating host immune defense to maintain a balanced periodontal microecology. Bitter taste receptors can serve as key targets for regulating periodontal homeostasis. Topical treatment with exogenous bitter tastants could effectively boost the secretion of periodontal antimicrobial peptides mediated by bitter taste receptors and prevent excessive bacterial colonization within the periodontal microecology in animal experiments.¹⁰⁷

By analysis of two single-cell RNA sequencing datasets from human periodontal tissues,^108,109 we observed a significant expression of bitter taste receptors in periodontal fibroblasts.²⁰ Subsequently, through in vitro culturing of human gingival fibroblasts, we successfully validated the presence of a wide range of bitter taste receptors.¹¹⁰ Our functional study revealed that activation of TAS2R16 could effectively counteract the NF-κB signaling pathway activated by LPS and subsequently reduce the expression levels of inflammatory factors such as IL-8, thereby mitigating chemotaxis of neutrophils.¹¹⁰ This particular function exhibited by TAS2R16 in gingival fibroblasts may play a crucial role in periodontal inflammation resolution, as partially demonstrated in our recently published animal study.¹¹¹ Further investigations are warranted to elucidate the endogenous ligands capable of activating TAS2R16 or other functionally similar bitter taste receptors during periodontal inflammation resolution.

Pathogen infections

Taste GPCRs can function as chemoreceptors that not only detect chemicals known as tastants to initiate taste signaling but also recognize microorganisms such as bacteria, thereby activating downstream signaling cascades, contributing to innate host defense. Research on the functions of taste receptors related to innate immunity has primarily focused on a specific group of taste-like cells, commonly referred to as tuft cells in certain tissues (e.g. intestine and urinary tract) and SCCs in others (e.g. periodontal tissue and respiratory tract). Additionally, in other cell types such as epithelial cells and macrophages, the function of taste GPCRs is also associated with innate immunity. We will discuss recent advancements in understanding the roles of taste GPCRs in relation to pathogen infection across various organs and tissues.

Respiratory tract infections

In the upper respiratory tract, SCCs were observed in scattered locations such as the nasal respiratory epithelium, the entrance of the vomeronasal canal, and the larynx. Among these locations, SCCs of the nasal respiratory epithelium have been extensively studied. These cells primarily express TAS2Rs, with a relative low expression of TAS1Rs.¹¹² Nasal SCCs were first identified in mice. Inhaled stimuli stimulate TAS2Rs on mouse nasal SCCs which then activate trigeminal nerves connected synaptically with them, resulting in changes in respiratory rate and triggering protective reflexes like apnea and sneezing,¹¹³ and releasing of antibacterial agents.^14,113 Additionally, activation of SCCs leads to the release of neurotransmitters from trigeminal nerve terminals, which in turn induces mast cell degranulation and plasma extravasation. This process ultimately results in neurogenic inflammation within the nasal cavity.¹¹⁴

In the human sinuses, SCCs are present at a low density, approximately 1 in every 100 sinus epithelial cells.¹¹⁵ Despite their limited abundance, they play a crucial role as immune sentinels. In human primary sinonasal air-liquid interface cultures and tissue explants, Lee RJ et al. found that TAS2R activation in SCCs triggered calcium waves that propagate via gap junctions to the surrounding ciliated epithelium, stimulating the secretion of antimicrobial peptides. Conversely, activation of sweet taste receptor (TAS1R2 and TAS1R3) in SCC inhibits TAS2R-mediated calcium waves to maintain normal airway immune homeostasis, until depletion of glucose in the airway surface due to infection, which releases the inhibition of TAS1R-signaling on TAS2R-mediated immune response.¹⁵ Interestingly, common nasal colonizers can exploit this natural regulatory mechanism to evade immunity. Lee RJ et al. demonstrated that Staphylococcus-produced D-amino acids can activate SCC sweet taste receptors and inhibit TAS2R-mediated innate defense.¹¹⁶

In mice, SCCs are widely distributed throughout the lower respiratory tract, including the lungs.¹¹⁷ Tracheal SCCs express a diverse array of taste receptors, particularly TAS2Rs. When stimulated by AHL, these receptors can elevate intracellular Ca²⁺ levels, thereby promoting acetylcholine release and facilitating nerve impulse conduction along vagus nerve endings associated with tracheal SCCs. Consequently, this mechanism inhibits respiratory rate.¹¹⁸ In addition, thymic stromal lymphopoietin (TSLP) is highly expressed in tracheal SCCs in mice, indicating that SCC serves as a significant source of IL-25 and cysteine leukotriene within the trachea.¹¹⁷ This suggests that tracheal SCCs may play a crucial role in the pathogenesis and progression of chronic inflammatory diseases such as asthma and eosinophilic pneumonia. A recent study in mouse model also found SCCs (named tuft cells in the study) in the injured lung have been demonstrated to facilitate inflammation resolution and tissue repair in H1N1-infected lung.¹¹⁹ Although they did not establish a direct link between the taste GPCRs expressed by lung SCCs and their role in this process, they verified that G protein subunit Gγ13, a downstream protein of the taste GPCRs, is indispensable.¹¹⁹

Nasal ciliated epithelial cells have been demonstrated to express TAS2R4, TAS2R43, TAS2R38 and TAS2R46.¹⁶ The quorum sensing molecules N-butyryl-L-homoserine lactone (C4-HSL) and N-3-oxo-dodecanoyl-L-homoserine lactone (C12-HSL), which are produced by Pseudomonas aeruginosa, a common nasal pathogen, can activate TAS2R38 of nasal ciliated epithelial cells and mediate downstream innate immune responses.¹²⁰ This includes promoting the release of antimicrobial peptides from neighboring cells¹¹⁵ and stimulating nitric oxide (NO) production by nasal epithelial cells to exhibit bactericidal effects, promotion of cilia movement and releasing of mucus to defend against pathogen infections.¹²¹ Takemoto K et al. discovered that TAS2R38 is associated with specific subtypes of chronic rhinosinusitis (CRS), and its expression is significantly reduced in nasal polyps from patients with eosinophilic CRS (ECRS) as well as ethmoid sinus mucosa from patients with non-eosinophilic CRS (non-ECRS) compared to healthy subjects.¹²² Oral and nasal fractional exhaled NO levels were notably decreased in non-ECRS patients, suggesting a complex involvement of TAS2R38 in ciliated cells related to specific CRS phenotypes.¹²² Furthermore, some studies have indicated that the polymorphism of TAS2R38 is linked to the severity of CRS. Functional (PAV) and non-functional (AVI) variants are observed for TAS2R38. Homozygous AVI/AVI individuals exhibit a diminished response to AHL compared to those homozygous PAV/PAV.¹²⁰ This genetic variation also leads to increased susceptibility to gram-negative upper respiratory tract infections¹²⁰ and a higher burden of biofilm formation.¹²³

Intestinal parasitic infections

Intestinal tuft cells have been identified as mediators of type II immune responses that facilitate the expulsion of parasites.¹²⁴ During parasitic infections, a positive feedback loop is established between intestinal tuft cells and type II innate lymphocytes (ILC2).^125,126,127 Intestinal tuft cells secrete IL-25 to activate ILC2 and produce type II cytokines like IL-5 and IL-13, which subsequently promote the differentiation of tuft cells and further secretion of IL-25, thus forming a reinforcing positive feedback loop. Evidence from transcriptome analysis and functional experiments suggests that GPCRs play a pivotal role in the ability of tuft cells to receive signals from the environment and transmit them to functional outputs.^17,128 The transcription analysis revealed the expression of taste GPCRs in tuft cells of various tissues, including mouse intestinal tuft cells.¹⁷ Taste GPCRs may serve as a crucial pathway for intestinal tuft cells to mediate type II immune responses.

Luo et al. discovered that mouse intestinal tuft cells expressed a diverse range of TAS2Rs, and infection with parasitic helminth Trichinella spiralis can induce tuft cell hyperplasia along with the increased expression of intestinal TAS2Rs.⁴⁸ However, whether the tuft cell hyperplasia is driven by TAS2Rs or other pattern-recognition receptors remains to be clarified. Additionally, they found that the clearance of parasite infection mediated by tuft cell-mediated type II innate immune response is dependent on TAS2Rs, as demonstrated using the TAS2R inhibitor allyl isothiocyanate. Heterologous expression assays also revealed that extracts from T. spiralis could activate the specific mouse bitter taste receptor Tsa2r143. Consistently, activation of Tas2r143 by salicin induced tuft cell expansion and type II innate immune response. These findings suggest that intestinal tuft cells recognize parasite infection through TAS2Rs and initiate the type II immune defense to eliminate parasites. In terms of downstream signaling mechanisms, their study proposed that TAS2R expressed by intestinal tuft cells function via G proteins G_α-gustducin/G_β1γ13 and G_αo/G_β1γ13. However, some studies have indicated that intestinal tuft cells do not express TAS2Rs. Miller et al., for instance, reported in experiments conducted on mouse small intestine tuft cells no expression of any known members from the TAS2R family.¹²⁹ Therefore, further animal studies are required to confirm whether intestinal tuft cells express TAS2Rs and their functionalities, and verification using human tissue samples is particularly important.

Although the study by Luo et al. did not directly identify sweet taste receptors in intestinal tuft cells, their findings suggest that the use of sweeteners enhances the tuft cell response to parasite infection imply a potential role for sweet taste receptors. Howitt et al. observed a significant tuft cell expansion in both BALB/c mice and C57BL/6 J mice when infected with the parasites Heligomomoides polygyrus (proximal small intestinal infection). However, when infected with the protozoa Tritrichomonas muris (distal small intestinal infection), the tuft cell response was merely observed in C57BL/6 J mice, not in BALB/c mice.¹³⁰ They hypothesized that this difference may be attributed to loss-of-function mutations in BALB/c TAS1R3 protein. Subsequently, they confirmed high expression levels of TAS1R3 specifically in the distal small intestine (ileum) and identified it as the most highly expressed taste GPCR in ileal tuft cells.¹³⁰ Mechanistic studies revealed that TAS1R3 knockout resulted in decreased gut Tuft cell numbers at homeostasis and impaired tuft cell response upon stimulation from parasites or succinate.¹³⁰ The specific mechanism underlying these observations remains unknown. Further exploration is warranted to determine if it involves binding between TAS1R3 and glucose or other intestinal contents to activate downstream pathways. Of note, Howitt et al. found weak expression levels of TAS1R1 and TAS1R2 in isolated ileal tuft cells.¹³⁰ The expression of TAS1R2 in the intestine is also suggested to be either absent or significantly low by some researchers.^131,132,133 Therefore, it is worth exploring whether TAS1R3 plays a role in gut tuft cells independently from TAS1R2, such as through the formation of homodimers or heterodimers with another Class C GPCR.

Urinary tract infections

Urinary tract infection is one of the most prevalent diseases affecting the urinary system and a significant risk factor for severe kidney disease and male infertility.¹³⁴ In their study, Deckmann et al. identified urethral tuft cells in close proximity to the urethral opening and at the end of glandular ducts within the urethra.¹⁸ They found that isolated mouse urethral tuft cells expressed Tas1r1, Tas1r3, and Tas2r108, while Tas1r2 was not detected. The majority (86%) of these tuft cells responded to exogenous glutamate, denatonium, and heat-killed uropathogenic E. coli. However, saccharin did not elicit any response in mice urethral tuft cells. Furthermore, under denatonium stimulation, acetylcholine released by rat urethral tuft cells acts on adjacent sensory nerve fibers to enhance bladder detrusor activity, aiding in the removal of harmful substances from the urethra and preventing bacterial colonization. Recently, through transcriptome analysis conducted by Deckmann’s group, it was discovered that both TAS1R2 and TAS1R3 are expressed in urethral tuft cells.¹⁹ By examining changes in intracellular Ca²⁺ concentrations in isolated mouse urethral tuft cells upon glucose stimulation, researchers observed that 78% of these cells responded to sucrose while 65% responded to fructose. To investigate the role of TAS1R3 in urine glucose recognition further, they compared wild-type mice with TAS1R3 knockout mice and found a significantly reduced proportion of responsive urethral tuft cells as well as diminished intracellular Ca²⁺ changes after sucrose stimulation in the latter group. Additionally, when treating mice with gurmarin, an inhibitor targeting mouse TAS1R3, there was a notable decrease in sucrose-induced responses among their urethral tuft cells. However, neither the knockout of the TAS1R3 gene nor the application of the inhibitor gurmarin could completely abolish the response of urethral tuft cells to sucrose, indicating that there exists an alternative “sweet” detection pathway in urethral tuft cells that is independent of TAS1R3. Similarly, in animal experiments, they discovered that transurethral instillation of sucrose and glucose could stimulate acetylcholine secretion by urethral tuft cells and significantly enhance bladder detrusor contractile activity in rats compared to saline. However, when combined with the TAS1R3 inhibitor gurmarin, sucrose and glucose did not enhance bladder detrusor contractile activity. This suggests that after sugar stimulation, urethral tuft cells enhance bladder detrusor activity in a manner dependent on TAS1R3. The increase in urine glucose concentration caused by diabetes is also a risk factor for urinary tract infections, and 50% of diabetic patients experience bladder dysfunction, cystopathy, and overactive bladder.¹³⁵ These conditions may be associated with the glucose recognition mechanism of urethral tuft cells. Currently, it remains unclear how taste receptor activation promotes bladder contraction, and there are limited studies on the function of urethral tuft cells and taste GPCRs.

Metabolic diseases

Metabolic diseases refer to a broad category of disorders resulting from systemic metabolic dysfunctions rather than a single condition, including but not limited to type 2 diabetes (T2D) and obesity. Deregulated glucose homeostasis is one of the key pathogenic mechanisms underlying these diseases.¹³⁶

Enteroendocrine cells (EECs) can sense glucose and other substances through taste GPCRs, thereby regulating the secretion of related hormones, maintaining glucose homeostasis, and contributing to the development of metabolic diseases. EECs can be classified into eight subtypes, commonly designated as S, I, L, K, D, N, A, and enterochromaffin cells.¹³⁷ Notably, the A, K, and L cell subtypes can express receptors for sweet, bitter, and umami tastes.¹³⁸ Glucagon-like peptide-1 (GLP-1) and GLP-2 are intestinal hormones secreted by L cells. GLP-1 enhances insulin secretion from the pancreas following oral glucose intake, whereas GLP-2 exerts its effects by facilitating intestinal glucose absorption.^22,139 Therefore, GLP-1 receptor agonists and GLP-1 analogues have emerged as viable therapeutic options for diabetes and obesity management.¹⁴⁰ In addition, ghrelin and cholecystokinin (CCK) are two important gastrointestinal hormones. Ghrelin accelerates gastric emptying and inhibits insulin secretion, while CCK regulates blood glucose levels by suppressing appetite and delaying gastric emptying.¹⁴¹ Glucose induces the secretion of GLP-1 by L cells, involving several glucose sensors, including sweet taste GPCRs, sodium-glucose cotransporter 1 (SGLT-1), and glucose transporter 2 (GLUT2). Huang et al. discovered that the effects of different glucose concentrations on STC-1 cell GLP-1 secretion and the protein levels of SGLT1, GLUT2, and sweet taste GPCRs were different, and they found that SGLT1 mainly participates in the induction of GLP-1 secretion by low glucose concentrations, while sweet taste GPCRs and GLUT2 mainly participate in the induction of GLP-1 secretion by high glucose concentrations.¹⁴² Margolskee et al. proved that TAS1R3 and gustducin are expressed in EECs and are the basis for sensing sugar and regulating SGLT1.²³ They found that compared to low-sugar diet, wild-type mice had increased expression of SGLT1 mRNA in high-sugar diet, while the expression of SGLT1 mRNA in TAS1R3 and gustducin knockout mice was consistent with that of wild-type mice on low-sugar diet, suggesting that there is an independent pathway that maintains the basal expression of SGLT1 mRNA. The expression of GLP-1 in the human intestinal endocrine L cell line NCI-H716 was confirmed by immunofluorescence staining and RT-PCR. Additionally, relevant taste signaling components were detected within this cell line. Stimulation of NCI-H716 cells with sucrose, glucose, or sucralose resulted in a concentration-dependent release of GLP-1 into the culture medium. The application of Lactisole, a sweet taste inhibitor targeting TAS1R3, inhibited the reactive release of GLP-1 in response to sucralose and also reduced the expression of gustducin in NCI-H716 cells. It was observed that glucose-mediated secretion of GLP-1 was diminished. Thus, both TAS1R3 and gustducin are involved in mediating sweetener-induced secretion of GLP-1 from NCI-H716 cells.²² Smith et al. proposed that besides GLP-1, GLP-2 is also implicated in taste GPCRs-mediated glucose metabolism. The intestinal TAS1R2/TAS1R3 can enhance glucose absorption by activating GLUT2 transporters mediated by GLP-2, facilitating GLUT2 translocation to the apical membrane of enterocytes.¹³⁹ Furthermore, they found reduced glucose absorption both in vivo in TAS1R2 knockout mice and ex vivo in intestinal organoids. However, the administration of teduglutide (a GLP-2 analog) completely restored intestinal glucose absorption. This indicates that GLP-2 acts as a downstream effector of TAS1R2 signaling. In conjunction with previous studies on GLP-1, they suggest that TAS1R2-mediated secretion of both GLP-1 and GLP-2 jointly regulates postprandial glucose levels. In addition, some preliminary studies suggest that the intestinal TAS2Rs may be involved in regulating glucose homeostasis. Researchers have proposed a relationship between TAS2Rs and the release of ghrelin, CCK, and GLP-1.¹⁴³ For example, oral administration of bitter gourd extract to high-fat-fed mice was shown to stimulate GLP-1 and insulin secretion following either oral or intraperitoneal glucose injection, resulting in reduced postprandial blood glucose levels. This effect could be inhibited by the specific GLP-1 receptor antagonist exendin-9.¹⁴⁴ The in vitro induction of GLP-1 secretion by STC-1 induced by bitter gourd extract was partially abolished by TAS2R inhibitor (probenecid) and PLCβ2 inhibitor (U-73122).¹⁴⁴

The pancreas also expresses sweet taste GPCRs as sweetness sensors, which may regulate the release of insulin as an independent signaling pathway from nutrient metabolism.^145,146 The expression and function of sweet taste GPCRs in the β cells play an important role in regulating basal insulin release, especially in regulating basal insulin release in the short-term fasting glucose concentration, sweet taste GPCRs sense the glucose and inhibit insulin secretion over time. On the contrary, in diabetic and diet-induced obese mouse models, the expression and function of sweet taste GPCRs are reduced, leading to an increase in basal insulin, which can offset the peripheral insulin resistance during the development of diabetes.¹⁴⁵ There is a difference among researchers on whether the sweet taste GPCRs in the pancreas function as typical TAS1R2/TAS1R3 heterodimers or TAS1R3 homodimers. The Kojima research group discovered that the mRNA and protein levels of TAS1R3 in mouse pancreatic tissue and MIN6 cells were significantly higher than those of TAS1R2, with the mRNA level of TAS1R2 being less than 1% of that of TAS1R3. Immunofluorescence analysis was unable to detect any presence of TAS1R2 protein. Following the knockout of TAS1R3, artificial sweeteners failed to further enhance glucose-induced insulin secretion in MIN6 cells. However, the knockout of TAS1R2 did not have a significant impact on this process.^147,148,149 Consequently, they proposed that the homologous dimerization of TAS1R3 may function as a glucose sensor on the surface of pancreatic β cells. Conversely, other researchers hold differing views. Kyriazis et al. identified expression for both TAS1R2 and TAS1R3 in human pancreatic islets and their role in mediating fructose’s enhancement effect on insulin secretion. In β cells from mice lacking TAS1R2, fructose-induced calcium influx and insulin release were diminished. Therefore, they posited that the heterodimeric structure formed by TAS1R2/TAS1R3 plays a critical role within β cells.^145,146 The expression of TAS2Rs in β cells and their potential role in regulating insulin release remains an underexplored area of research. Some studies have indicated that denatonium, can stimulate insulin secretion from rat pancreatic islets. However, the effects of denatonium on β cells do not appear to be mediated by the activation of TAS2R receptors or gustducin.¹⁵⁰ Current investigations into the expression and function of taste GPCRs in the pancreas predominantly focus on animal models and cellular experiments. The implications of these findings for human physiology remain uncertain. Therefore, further research is necessary to elucidate the role of taste GPCRs-mediated regulation of insulin release within human physiological contexts and its interactions with other established mechanisms governing insulin regulation.

Diabetes mellitus is a complicated endocrine disease characterized by hyperglycemia.¹⁵¹ A study has indicated that the expression of intestinal sweet taste GPCRs in T2D patients is negatively correlated with fasting blood glucose levels.¹³⁹ However, it should be noted that under conditions of rapid fluctuations in luminal glucose levels, sweet taste GPCRs expression may be influenced. Yang et al. employed a randomized crossover design involving healthy subjects and T2D patients and found that the absolute transcription levels of sweet taste GPCRs were not significantly affected by acute changes in fasting blood glucose but were responsive to luminal glucose exposure.¹⁵² Specifically, normal glycemic conditions exposed to luminal glucose resulted in increased TAS1R2 expression. Conversely, hyperglycemic states led to decreased TAS1R2 expression. In contrast, exposure to luminal glucose in T2D patients resulted in elevated TAS1R2 expression. This suggests that dysregulation of sweet taste GPCRs expression may contribute to persistent postprandial hyperglycemia observed in individuals with T2D. Quinoa has been reported to possess notable glucose-lowering properties. To explore its mechanism of action, researchers administered quinoa to T2D mouse models induced by a high-fat diet (HFD) combined with streptozotocin (STZ). They observed that compared to normal control mice, T2D mice exhibited increased expression of TAS1R3 and TRPM5 in the colon, while GLP-1 expression was reduced. Both quinoa and metformin were able to reverse these changes. Thus, they hypothesized that one mechanism through which quinoa ameliorates hyperglycemia is via nutrient sensing through taste GPCRs.¹⁵³ Furthermore, there is evidence indicating potential alterations in bitter taste receptor expression among diabetic patients as well. Bartakova et al. compared the genotypes related to bitter taste receptors between pregnant women with gestational diabetes and healthy pregnant controls and found a lower frequency of the TAS2R9 rs3741845 allele among those with gestational diabetes.¹⁵⁴ Also, a study has suggested that the rs3741845 SNP of TAS2R9 results in an alanine-to-valine substitution at position 187 (Ala187Val) in the predicted ligand-binding pocket, leading to a defective response to certain bitter ligands and subsequently affecting glucose homeostasis.¹⁵⁵

It has been reported that there is a notable correlation between obesity and taste GPCRs. A recent review elucidates how individuals can consume sweet substances, triggering feelings of satisfaction through central reward pathways.¹⁵⁶ The authors emphasize that sugar may induce addiction similarly to nicotine, leading to dulled taste perception among obese populations. Furthermore, they found that inhibiting sweet or umami perception could facilitate weight loss. Interestingly, the authors note that while non-nutritive sweeteners may result in short-term weight reduction, the prevalence of obesity and metabolic dysfunction continues to rise. This trend may be associated with an increased risk of disease linked to the use of non-nutritive sweeteners. Additionally, previous research by Liszt et al. indicates that obesity alters TAS2R expression in intestinal cells in a region-dependent manner and reduces EECs sensitivity to TAS2R agonist denatonium benzoate concerning ghrelin expression.¹⁵⁷ Obesity may also influence TAS2R expression and sensitivity in other cell types, such as Paneth cells and goblet cells.

In conclusion, there exists a significant relationship between digestive system taste GPCRs and metabolic diseases. An increasing body of evidence suggests that taste GPCRs are substantially involved in nutrient sensing, monitoring changes in energy storage, and initiating metabolic and behavioral responses essential for maintaining energy balance. By targeting taste GPCRs, novel drugs with specificity and efficacy can be developed for improved management of body weight and glucose homeostasis.

Asthma

Airway smooth muscle cells (ASM) express a variety of TAS2Rs. Interestingly, under the stimulation of bitter compounds, ASM cells exhibit severe relaxation instead of contraction. This implies that bitter taste receptor agonists act as bronchodilators and are three times more effective than β-adrenergic receptor agonists.⁵⁰ The underlying mechanisms include: 1) TAS2R-mediated increase in intracellular Ca²⁺, accompanied by BK_Ca channel-mediated increase in Ca²⁺-dependent K⁺ conductance, leading to membrane hyperpolarization and relaxation.⁵⁰ 2) Separation of the G_βγ subunit, thus inhibiting the voltage-dependent Ca²⁺ channels (VDCC).⁵¹ 3) Dissociation of TAS2R-coupled G protein G_αt from the Tas2R-G_αt/G_βγ complex, with the released G_αt binding to acetylcholine receptors (AChR), competitively inhibiting the function of coupled G protein Gq and preventing AChR-induced Ca²⁺ signaling.⁵² 4) Inhibition of RhoA activity and myosin light chain phosphatase (MYPT)1 phosphorylation at the T853 residue modulating histamine-induced myosin light chain (MLC)20 phosphorylation, leading to relaxation of contracted ASM.⁵³ In addition to these mechanisms, TAS2R agonists have concentration-dependent anti-mitogenic effects on ASM and can treat asthma by alleviating ASM remodeling.¹⁵⁸ Furthermore, TAS2R agonists also regulate immune cells during asthma. For example, they inhibit pro-inflammatory factor release by macrophages¹⁵⁹ and polarize them towards M2 type.¹⁶⁰ Additionally, TAS2R agonists like denatonium and chloroquine can inhibit IgE-dependent mast cell activation, thereby alleviating asthma symptoms.¹⁶¹ Therefore, TAS2Rs are considered potential targets for anti-asthma therapy. However, it is important to note that in an animal study, researchers observed no significant difference in bronchodilation induced by bitter tastants between wild-type mice and their corresponding TAS2R knockout counterparts (Tas2r143/Tas2r135/Tas2r126 triple knockout).¹⁶² This finding suggests that the mechanism of bronchodilation mediated by bitter tastants in mice may operate independently of TAS2Rs.

However, the lack of tested safe and effective agonists that act at low effective concentrations has hindered the clinical approval of TAS2R-based agents for asthma treatment. Nevertheless, certain drugs approved for asthma treatment, such as the macrolide antibiotic azithromycin,¹¹² the anti-inflammatory analgesic flufenamic acid, and the antihistamine diphenhyramine,¹⁶³ have shown potential as TAS2R ligands. A recent study utilizing BitterDB database identified flufenamic acid as a highly effective compound capable of rapidly activating TAS2R14 and leading to ASM relaxation at a low concentration (1 μM).¹⁶⁴ Of note, as aforementioned, the protein structures of two complexes formed by TAS2R14 with gustducin and G_i1 were resolved, providing insights into ligand recognition of TAS2Rs and laying the foundation for future development of TAS2R-based anti-asthma drugs.^85,86

Reproductive dysfunction

In the male reproductive system, taste GPCRs may play a crucial role in sperm chemotaxis, fertility, and sterility.¹⁶⁵ As early as 2001, Max et al. identified TAS1R3 expressed in mouse testes.⁵ Subsequently, researchers discovered gustducin, a key component of taste transduction, in mammalian spermatozoa.¹⁶⁶ Mosinger et al. discovered that both genetic deletion and pharmacological blockade of the TAS1R3 receptor result in reproductive disorders in male mice. These alterations include decreased sperm count, abnormal sperm morphology, and impaired sperm motility within the testes, highlighting the crucial involvement of TAS1R3 in spermatogenesis and sperm function.¹⁶⁷ Moreover, bitter tastants such as chemokines or progesterone secreted by cumulus–oocyte complex have the potential to activate TAS2Rs in spermatozoa and promote sperm chemotaxis, capacitation, and acrosomal reactions.¹⁶⁸ Although these studies indicate the presence of taste GPCRs in the reproductive system and suggest their potential role in reproductive function, there is currently no clear evidence regarding endogenous ligands under physiological conditions, and a lack of comprehensive functional studies to determine their role under such conditions. Li and Zhou found that the absence of TAS2R5+ cells resulted in testicular shrinkage and male infertility in mice.¹⁶⁹ Additionally, a study demonstrated that non-synonymous SNPs of TAS2R14 and TAS2R3 were associated with decreased sperm motility and structural abnormalities.¹⁷⁰ Polycystic ovary syndrome (PCOS) is one of the most prevalent reproductive disorders among women. Wu et al. discovered that using agonists for Tas2r108 effectively improved endocrine and metabolic disorders associated with PCOS while promoting recovery of reproductive function.¹⁷¹ Currently, further exploration is needed to understand the mechanism behind taste GPCRs’ involvement in reproductive dysfunction.

Neurodegenerative diseases

Taste receptors, including TAS1Rs, TAS2Rs, and their downstream effector proteins, have been detected in various regions of the central nervous system (CNS), suggesting a neuromodulatory role beyond gustation.^172,173,174 Many neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), share overlapping mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and protein misfolding.¹⁷⁵ Under normal conditions, TAS2Rs-mediated sensing of pathogenic, toxicogenic, and microbial molecules in the brain is crucial for preventing neuroinflammatory responses and supporting immune system function.²⁶ Accordingly, dysfunctional signaling or downregulation of key components of the taste signaling pathway has been associated with the cellular damage characteristic of neurodegenerative diseases. Although sweet receptors were once believed to function primarily in learning and memory, recent evidence indicates that disruptions in sweet taste receptor signaling are also linked to inflammatory responses.^176,177,178 Thus, sweet taste receptor signaling may contribute to neuroinflammation as well.

Alzheimer’s disease

AD is one of the most common neurodegenerative disorders, characterized by progressive and irreversible cognitive decline, ultimately compromising patient independence.¹⁷⁹ In AD, pathophysiological changes involving protein alterations lead to oxidative stress, dysfunction across multiple cellular pathways and cell death. Although many studies describe the neuroprotective effects of bitter compounds in AD, the role of TAS2Rs in mediating these effects remains unclear. For example, bitter compounds have been reported to reduce apoptosis, inflammation, and oxidative stress by regulating inflammatory markers (TNF-α, IL-1β, iNOS) and antioxidant enzymes (superoxide dismutase, glutathione, catalase).^{180,181,182,183} Alves et al. reported a correlation between TAS2Rs expression and AD progression: TAS2Rs genes, along with other AD-associated genes, were progressively downregulated from the early stages of AD, with continued decline as the disease advanced.¹⁸⁴ These findings suggest that TAS2Rs may serve as both potential biomarkers and therapeutic targets, warranting further investigation.

Parkinson’s disease

PD, the second most prevalent neurodegenerative disorder after AD, results from the progressive loss of dopaminergic neurons in the substantia nigra and striatum of the midbrain.¹⁸⁵ This neuronal degeneration is driven by α-synuclein accumulation, which triggers neuroinflammation and neurodegeneration in PD by inducing degrading enzymes, inflammatory mediators and NLRP3 inflammasome activation.¹⁸⁶ NF-κB and the NLRP3 inflammasome are central regulators of inflammatory networks and contribute to both neuroinflammatory processes and TAS2Rs signaling dysregulation.^187,188 Defects in TAS2Rs signaling can lead to the overproduction of pro-inflammatory cytokines such as IL-1β, which further activate NF-κB via Toll-like receptor pathways.¹⁸⁹ Certain TAS2Rs agonists have been shown to mitigate lipopolysaccharide (LPS)-induced neuroinflammation, oxidative stress, and apoptosis by suppressing NLRP3 and NF-κB signaling.^{190,191,192,193,194} These findings suggest a potential role for TAS2Rs in mediating the protective effects of their ligands for treating CNS disorders. Furthermore, TAS2Rs expression has been reported to change in PD patients, with TAS2R5 and TAS2R50 downregulated, while TAS2R10 and TAS2R13 are upregulated.¹⁹⁵ Despite these researches, further research is needed to clarify the specific roles of TAS2Rs in PD pathophysiology.

Cancers

The expression of taste GPCRs has been detected in various types of tumor cells and is differentially expressed in tumor tissues. Ryan M et al. conducted an analysis on the expression of TAS1Rs and TAS2Rs in 45 types of solid tumors using data from TCGA, revealing that compared to normal tissues, TAS2R4, TAS2R5, TAS2R14, TAS2R19, TAS2R20, and TAS2R31 are generally downregulated in tumors while TAS1R3 and TAS2R38 are usually upregulated.¹⁹⁶ Furthermore, the correlation between taste GPCR expression levels and patient prognosis varies among different tumors. For instance, increased expression of TAS2R14 is associated with improved survival in non-papillary bladder cancer but decreased survival in adrenal cortex carcinoma and esophageal adenocarcinoma.¹⁹⁶ Therefore, taste GPCRs hold promise for tumor prognosis analysis and therapy. A study utilizing data from TCGA and GEO databases identified 7 TAS2Rs that are linked to the survival of colon cancer patients, leading to the definition of two molecular subtypes of colon cancer.¹⁹⁷ These subtypes exhibit low immune cell infiltration and poor prognosis when high levels of TAS2Rs are expressed, suggesting a potential association between TAS2Rs and tumor immune invasion to some extent. Moreover, the activation of pancreatic cancer cells TAS1R2/TAS1R3 by natural or artificial sweeteners can induce transactivation of glycosylated receptors, leading to the manifestation of tumor metastasis phenotypes such as epithelial mesenchymal transformation and enhanced cell migration, suggesting that the activation of sweet receptors in pancreatic cancer cells may be associated with cancer metastasis.¹⁹⁸ In contrast, Seo et al. demonstrated that TAS2R8 and TAS2R10, endogenously expressed in neuroblastoma (NB) cancer cells, play significant roles in suppressing cancer stemness, migration, and invasion by reducing matrix metalloproteinase-2 (MMP-2) activity, dampening hypoxia-related programs, and downregulating cancer stem cell (CSC) markers.¹⁹⁹ These findings are consistent with research by Wölfle’s team, which showed that salicin, a TAS2R16 agonist, promotes neurite outgrowth through bitter taste receptor activation.²⁰⁰ Additionally, a study has also demonstrated that gustducin can play a role in inhibiting pancreatic cancer.²⁰¹ Knockout of gustducin increases the expression of CXCL1 and CXCL2 in epithelial cells, thereby increasing the number of CXCR2+ myeloid suppressor cells.²⁰¹

Moreover, taste GPCRs offer novel targets for cancer treatment. For instance, the TAS2R14 agonist noskapine and diphenhydramine have demonstrated their ability to induce the pro-apoptotic effect in ovarian cancer cell line SKOV3.²⁰² Kaempferol is also recognized as a ligand of TAS2R14 and TAS2R39, which promotes apoptosis in human cervical cancer cells through the PI3K/AKT and telomerase pathways or in ovarian cancer cells via the death receptor/Fas associated death domain (FADD)/caspase-8 pathways.^203,204 In head and neck squamous cell carcinoma (HNSCC), particularly among patients with HPV infection, elevated expression of TAS2R14 has been observed. Lidocaine has been found to activate TAS2R14 and induce apoptosis of HNSCC cancer cells, thereby exhibiting therapeutic potential.²⁰⁵ Furthermore, it can enhance the apoptotic effect when combined with a GLUT1 inhibitor.²⁰⁶ Salvestrini et al. extended the relevance of taste GPCRs from solid tumors to hematologic malignancies. In their study, TAS2Rs expressed in AML cells were activated by denatonium (DEN), leading to suppressed proliferation and clonogenicity, induction of apoptosis, reduced migration, and altered metabolism. DEN exerted these effects by activating 9 out of 25 TAS2Rs, five of which (TAS2R4, TAS2R8, TAS2R10, TAS2R13, and TAS2R30/47) were also expressed at protein level in both AML patient samples and AML cell lines.²⁰⁷ Therefore, taste receptor agonists may serve as promising avenues for cancer therapy. Additionally, overexpressed taste receptors offer new targets for drug design. Jessica et al. designed a TAS2R9-targeted liposome specifically aimed at delivering CXCR2 inhibitors to cancer-related fibroblasts within pancreatic ductal adenocarcinoma tissue to achieve therapeutic effects.²⁰⁸ However, these studies still lack specific genetic evidence that definitively elucidates the role of taste receptors in cancer research such as utilizing cell-specific knockout mice, thus they remain at an early stage of investigation with considerable distance from clinical drug development.

Conclusion

Taste GPCRs, particularly TAS1Rs and TAS2Rs, play multifaceted roles beyond taste perception, influencing metabolism, immunity, and cellular signaling across various tissues. Their dysfunctions and polymorphisms are closely linked to the pathogenesis of diseases such as metabolic disorders, respiratory infections, dental caries, and certain cancers. Advances in understanding their signaling mechanisms and structural characteristics have revealed critical insights into their physiological and pathological roles, highlighting their potential as therapeutic targets. This review underscores the importance of taste GPCRs as regulators of systemic processes and advocates for further exploration of their functions in non-taste tissues. Despite challenges in resolving their structural complexity and understanding their interactions in diverse physiological contexts, ongoing research and technological advancements offer new opportunities for therapeutic innovation. By targeting these receptors, it may be possible to develop novel treatments for a range of diseases, from metabolic and immune disorders to cancer. Continued investigation into the molecular mechanisms of taste GPCRs will undoubtedly deepen our understanding of their contributions to health and disease.