Next Article in Journal
Fused Cells between Human-Adipose-Derived Mesenchymal Stem Cells and Monocytes Keep Stemness Properties and Acquire High Mobility
Next Article in Special Issue
Identification of Candidate Chemosensory Gene Families by Head Transcriptomes Analysis in the Mexican Fruit Fly, Anastrepha ludens Loew (Diptera: Tephritidae)
Previous Article in Journal
Absence of Gut Microbiota Is Associated with RPE/Choroid Transcriptomic Changes Related to Age-Related Macular Degeneration Pathobiology and Decreased Choroidal Neovascularization
Previous Article in Special Issue
Functional Characterization of the Venus Flytrap Domain of the Human TAS1R2 Sweet Taste Receptor
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 17
10.3390/ijms23179677
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Taste Receptors beyond Taste Buds

by
Su Young Ki
1 and
Yong Taek Jeong
1,2,*
1
Department of Pharmacology, Korea University College of Medicine, Seoul 02841, Korea
2
BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(17), 9677; https://doi.org/10.3390/ijms23179677
Submission received: 30 July 2022 / Revised: 18 August 2022 / Accepted: 24 August 2022 / Published: 26 August 2022
(This article belongs to the Special Issue Molecular and Cellular Mechanisms Underlying Taste, Smell and Beyond)
Review Reports Versions Notes

Abstract

:
Taste receptors are responsible for detecting their ligands not only in taste receptor cells (TRCs) but also in non-gustatory organs. For several decades, many research groups have accumulated evidence for such “ectopic” expression of taste receptors. More recently, some of the physiologic functions (apart from taste) of these ectopic taste receptors have been identified. Here, we summarize our current understanding of these ectopic taste receptors across multiple organs. With a particular focus on the specialized epithelial cells called tuft cells, which are now considered siblings of type II TRCs, we divide the ectopic expression of taste receptors into two categories: taste receptors in TRC-like cells outside taste buds and taste receptors with surprising ectopic expression in completely different cell types.

1. Introduction

The chief function of chemosensory receptors is to recognize exogenous compounds, convert their chemical signals into biologic responses, and generate chemosensory information. Therefore, primary chemosensory tissues, such as the olfactory epithelium and the taste buds, express olfactory and taste receptors, respectively. Chemosensory receptors are also expressed, however, in organs unrelated to sensory perception. This expression was initially considered misregulation and was thus dubbed “ectopic expression”. Since then, new evidence has accumulated suggesting these ectopic chemosensory receptors play other roles. This review focuses mainly on the function of taste receptors expressed outside of taste buds. First, we briefly describe the history of taste receptor research. Then, we describe taste receptor-coupled signaling pathways before finally exploring ectopic taste receptor expression in TRC-like cells outside taste buds as well as genuine ectopic expression. This review paper only refers taste receptors, the subclass of G protein-coupled receptors superfamily, as “taste receptors”, excluding the ion channels involved in the transduction of salty and sour taste.

2. Classical View on Taste Receptors

2.1. Discovery of Taste Receptors

Taste receptors were first identified via a subtractive cDNA library screen performed on rodent taste bud-containing tissues [1,2]. A similar strategy had already proven successful in the discovery of the olfactory receptors (ORs) and vomeronasal receptors (VRs) in the olfactory mucosa [3,4]. The first taste receptor screen identified TR1 and TR2, later renamed Tas1r1 and Tas1r2, respectively [5]. Sequence analysis of Tas1r1 and Tas1r2 implied their membership in the GPCR superfamily as siblings of the ORs and metabotropic glutamate receptors (mGluRs) [2]. Further screening revealed a group of sequences similar to Tas1r1 and Tas1r2, and these were dubbed Tas2rs [5].
Meanwhile, Tas1r3 was discovered via a different approach [6,7,8,9,10]. Mouse geneticists had already mapped the Sac locus on the tip of mouse chromosome 4 as a determinant of behavioral preference toward sweet taste stimuli [11]. Then, six independent groups suggested that a single Gpr70-encoding gene near the Sac locus encodes a novel taste receptor family [6,7,8,9,10,12]. Genetic rescue experiments that introduced a taster allele of Tas1r3 into homozygous non-taster animals finally proved this to be true.
Together, three Tas1rs and 25 (in humans) or 35 (in mice) Tas2rs have been identified. It is now widely accepted that Tas1r3 acts as a co-receptor for sweet and umami taste receptors in combination with Tas1r2 or Tas1r1 [12,13], respectively. Tas2rs, in contrast, function as bitter taste receptors [14,15].

2.2. Signal Transduction Pathways for Taste Receptors

After taste receptors were identified at the molecular level, amino acid-level sequence comparisons of taste receptors indicated that they possess seven transmembrane domains [1,2] and suggested they likely function as GPCRs. First, sweet, bitter, and umami tastants trigger intracellular increase in Ca2+ [16] or decrease in cyclic adenosine monophosphate (cAMP) concentrations [17,18] in type II TRCs. Second, type II TRCs express molecular players for GPCR pathways such as Gβ3 [19], Gγ13 [20], α-gustducin (GNAT3) [18,21,22,23], phospholipase Cβ2 (PLCβ2) [21], and transient receptor potential M5 (TRPM5) [21,24]. Lastly, in vivo mouse studies of genetic knockouts confirm their significance in the cellular responses to tastants [18,21,23].
Despite being activated by different types of tastants, Tas1rs and Tas2rs couple to the same intracellular signaling pathway via a heterotrimeric G protein [21]. When the receptors are activated by bitter or sweet compounds, the α subunit GNAT3 dissociates from its β and γ subunit partners, which then activate downstream signaling via PLCβ2 and the inositol 1,4,5-trisphosphate (IP3) pathway. These trigger cytoplasmic Ca2+ release [19,20]. IP3 triggers Ca2+ release from the endoplasmic reticulum via the IP3 receptor [25]. The Gα subunit activates phosphodiesterases, which reduce cAMP levels [26]. This reduces protein kinase A (PKA) activation. Without this inhibition [27], PKA prevents the IP3 pathway from inducing further Ca2+ efflux from the endoplasmic reticulum [28]. Once released, cytoplasmic Ca2+ ions open the TRPM5 channel [29,30,31], resulting in Na+ influx [32]. This triggers the opening of the voltage-gated Na+ channels that mediate action potential generation [33]. Action potentials trigger the release of the neurotransmitter ATP via a non-vesicular mechanism mediated by a heteromeric complex of calcium homeostasis modulator 1 (CALHM1) [34] and CALHM3 [35]. The secreted ATP then activates taste cells and sensory fiber receptors, leading to the transmission of taste sensation to the central nervous system [36,37].

3. Categorizing Ectopic Taste Receptor Expression

3.1. Taste Receptors Expressed in TRC-Like Cells Outside Taste Buds

Tuft cells are a rare population of epithelial cells named for their characteristic morphology, including a specialized tubulovesicular system and a “tuft” of long, blunt microvilli projecting from a narrowed apical face [38]. Tuft cells are broadly distributed across the epithelial mucosa, such as the oral cavity [39], alimentary tract [40,41,42,43,44], upper and lower respiratory tracts [45,46,47,48], and even the thymus [49,50]. Depending on their location, tuft cells can also be referred to as brush cells [51,52] or solitary chemosensory cells (SCCs) [39,45,46,53,54]. Recently, tuft cells were divided into two groups [43,47]. Tuft-1 cells share very similar transcriptomic features with type II TRCs in taste buds, whereas tuft-2 cells show enrichment for immune-related genes [43,55]. Taste receptors and their downstream effectors are generally expressed in tuft-1 cells. This classification is valid across many organs, such as the intestines [43], the airways [47], and the thymus [49]. Further study of the tuft cells in other organs will improve these sub-classifications. Similar morphology, gene expression profiles, and developmental pathway [56,57,58] suggest that tuft cells are TRC-like cells. Therefore, we need to discriminate the expression of taste receptors in TRC-like cells from in other types of cells.

3.1.1. Intestinal Tuft Cells

Most studies of tuft cells have focused on those in the intestine. Intestinal tuft cells are crucial for defense against microbial challenges because they detect microbe-derived chemicals in the intestinal lumen. Upon activation, these tuft cells secrete interleukin 25 (IL-25) to drive the activation of type 2 innate lymphoid cells 2 (ILC2) [40,42,44,55,58]. Multiple research groups found that intestinal tuft cells exhibit a transcriptional repertoire similar to type II TRCs. The master transcription factor Pou2f3 is necessary for the generation of both intestinal tuft cells and type II TRCs [56,57,58]. Both cell types also share the downstream effectors required for taste receptor signaling. Even before the expression of taste receptors was discovered in intestinal tuft cells, their expression of the taste-specific GPCR signal transducers GNAT3, PLCβ2, and TRPM5 had already been reported, implicating them in chemosensation [44]. Later, transcripts encoding taste receptors were sporadically detected by RT-PCR [59]. More recently, single-cell RNA sequencing (scRNA-seq) experiments have also revealed taste receptor expression in intestinal tuft cells [43]. Tas1r3 seems to be expressed alone without its conventional binding partners, Tas1r1 or Tas1r2 [43]. Although bitter receptor expression was too low for detection in multiple single-cell data [41,43], RT-PCR and genetic lineage tracing experiments support their expression in intestinal tuft cells [59,60]. This discrepancy may be an artifact of the limited coverage of single-cell RNA sequencing. Alternatively, given that tuft cell expansion depends on the microbiome in such a way that basal expression levels of bitter receptors would presumably remain low in the normal state, it is possible that the discrepancy is due to differences in the microbiomes of various mouse cohorts. It also remains unclear whether Tas1r3 and bitter receptors are expressed in identical cell populations.
What about the function of taste receptors in intestinal tuft cells? The simplest hypothesis suggests that taste receptors detect various ligands inside the gut lumen. For example, bitter receptors offer appropriate molecular machinery for activating defensive responses to infection by the parasitic helminth Trichinella spiralis [59]. T. spiralis-derived compounds evoke intracellular Ca2+ responses in intestinal tuft cells, causing them to release IL-25. They then undergo hyperplastic expansion via a tuft cell-ILC2 circuit. T. spiralis infection increases the expression of several bitter receptors, including the salicin-responsive receptor Tas2r143. Salicin stimulation recapitulated tuft cell secretion of IL-25. In addition, stimulation with allyl isothiocyanate (AITC), which irreversibly antagonizes bitter receptors via an unknown mechanism, impaired IL-25 secretion. These results suggest bitter receptors can play a role in sensing unidentified parasite-derived molecules.
In contrast, Tas1r3, the most abundant taste receptor in the intestine, seems to have another function. Tas1r3-deficient mice have fewer intestinal tuft cells than wild-type control mice and mice with mutations in the chemosensory genes GNAT3 and PLCβ2 [61]. The cellular composition of the other types of intestinal epithelial cells, however, remained unaltered. Treatment of Tas1r3 knockout (KO) mice with IL-13 or succinate induced differentiation toward intestinal tuft cells, increasing the number of tuft cells to levels comparable to that of controls. This implies a role for Tas1r3 in the regulation of epithelial homeostasis independent from the canonical chemosensory and ILC2 pathways.

3.1.2. Respiratory Tuft Cells

The respiratory mucosa is another tissue with its own microbiome. Like the intestinal tuft cells, respiratory tuft cells receive microbe-derived molecules to regulate the airway immune system. In the upper respiratory mucosa, TRPM5-expressing SCCs are scattered across the sinonasal surface [54]. These SCCs are distinct from the conventional chemosensory cells in the olfactory mucosa. Pou2f3-deficient mice lack TRPM5 SCCs in the nasal cavity, implying that they follow a similar developmental program as tuft cells in other regions. Transcripts for bitter receptors are expressed in the nasal mucosa, and their expression is regulated by sinonasal infection [62]. Bitter tastants and Pseudomonas aeruginosa (P. aeruginosa)-derived quorum-sensing molecules such as LasI (3-oxo-C12-HSL) and EsaI (3-oxo-C6-HSL/C6-HSL) evoke Ca2+ responses in sinonasal SCCs [53]. Sinonasal SCC activation triggers the release of acetylcholine, which transiently suppresses spontaneous breathing events via nociceptive neurons in the area surrounding the SCCs [46]. Moreover, SCC activation also induces nasal inflammation via substance P, resulting in plasma extravasation and mast cell degranulation. Genetic loss of Gnat3 abolished all these phenomena, implicating the canonical taste receptor transduction pathway [53]. Sinonasal SCCs in humans express bitter receptors like their counterparts in mice, but human sinonasal SCCs also express Tas1r3 [45]. Interestingly, the function of Tas1r3 in these SCCs opposes that of the bitter receptors [45]. Glucose-mediated activation of Tas1r3 was found to alleviate cellular responses to the bitter tastant denatonium, and treatment with the specific Tas1r3 antagonist lactisole was found to disinhibit this inhibitory effect of glucose on the denatonium response.
In the lower respiratory tract, tracheal tuft cells are responsible for neurogenic inflammation induced by bacterial infection [52]. LasI not only activates intracellular Ca2+ responses in tracheal tuft cells, but it also induces extravasation and recruits neutrophils via secretion of calcitonin gene-related peptide and substance P. Denatonium can also induce neurogenic inflammation, suggesting the involvement of functional bitter taste receptors. All these phenomena are dependent on TRPM5. Thus, across both the upper and lower respiratory tracts, there seems to be a conserved role for bitter taste receptors in protecting against bacterial infections.

3.1.3. Gingival SCCs

The oral mucosa comprises the buccal mucosa, lingual mucosa, hard and soft palatal mucosa, and the gingiva. In addition to the type II TRCs in the taste buds on the surface of the tongue and soft palate, separate tuft cell-like structures were discovered in the gingival epithelium [39]. Gingival SCCs function as immune sentinels for periodontitis. Using bitter taste receptors and their corresponding downstream effectors, gingival SCCs recognize the quorum-sensing compound acyl-homoserine lactone (AHL), which is derived from the oral microbiome. Gnat3 ablation leads to severe alveolar bone loss upon gingiva ligature, an altered oral microbiome profile, and imbalanced expression of inflammatory and anti-inflammatory cytokines. Finally, the bitter tastant denatonium was found to slow the progression of periodontitis, suggesting novel strategies for preventing periodontal disease.

3.1.4. Thymic Tuft Cells

The thymus is responsible for the maturation of T lymphocytes. In the thymic medulla, thymic epithelial cells present antigens from peripheral tissues, mediating the development of central tolerance. Recently, scRNA-seq was used to explore the cellular diversity of thymic epithelial cells [49,50]. A minor population of thymic epithelial cells was discovered that exhibited a gene expression profile like that of peripheral tuft cells, including the expression of IL-25 and components of the canonical taste transduction pathway. Mice lacking Pou2f3, the master tuft cell regulator, lack these thymic tuft cells and produce fewer NKT2 cells, which are the cellular sources of IL-4. Given that IL-25 and IL-4 are crucial mediators of the ILC2 circuit, thymic tuft cells seem to contribute to the microenvironment necessary for immune system regulation. Thus, although thymic tuft cells do seem to promote immune tolerance for tuft cell-restricted antigens, it remains unclear whether or how bitter taste receptors contribute to this process [49]. If bitter taste receptors are involved, pharmacologic activation with bitter tastants or inhibition with AITC could prove useful as novel therapeutic strategies for immune regulation.

3.1.5. Urinary Tuft Cells

Since tuft cells in the intestine and airway secrete acetylcholine as a paracrine neurotransmitter, transgenic mice expressing eGFP in choline acetyltransferase (Chat)-expressing cells were used in the hunt for urethral tuft cells [51]. Urethral tuft cells adopt the canonical taste transduction cascade, including taste receptors, PLCβ2, and TRPM5. In addition, individual urethral tuft cells exhibit polymodal receptivity, responding to both sweet and bitter compounds. Application of tastants induced bladder detrusor activity, but this was blocked by co-application of the nicotinic receptor antagonist mecamylamine. Thus, urinary taste receptors and their downstream cascade seem to have a protective function in monitoring the contents of the urethral lumen.

3.1.6. Neoplastic Tuft Cells

Tuft cells appear in both normal and neoplastic tissues. Inevitably, cancer disturbs the structure and balanced heterogeneity of cellular composition in normal tissues as a single cell type expands and crowds out its neighbors. One research group proposed that intestinal tuft cells act as cancer stem cells [63], and it is possible that a similar process occurs in some cases of respiratory cancer. Small cell lung cancers (SCLCs) can be divided into biological variants according to their expression of biomarkers such as ASCL1, NEUROD1, YAP1, and POU2F3 [64]. While ASCL1high SCLCs show neuroendocrine-related profiles, the less common POU2F3high SCLCs often exhibit a tuft cell-like expression signature that includes SOX9, GFI1B, ASCL2, and TRPM5. Given that pulmonary and bronchial tuft cells express several taste receptors, it is possible that the abnormally expanded tuft cells in these tumors also express taste receptors. If so, tastants could prove useful in the clinic for cancer treatment, but this remains to be proven.

3.2. Genuine-Ectopically Expressed Taste Receptors

3.2.1. Enteroendocrine Cells

In the intestinal epithelium, enteroendocrine cells (EECs) detect various luminal nutrients to generate interoceptive hunger/satiety signals and modulate metabolic responses by secreting neuropeptides/hormones such as glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), serotonin (5-HT), etc. [65]. This nutrient-sensing capacity of EECs suggests the existence of EEC nutrient sensors. In this context, sweet and umami taste receptors are attractive candidates because they are already used for nutrient detection in TRCs in the mouth [66,67]. In exploring this hypothesis, several groups have employed the EEC-like cell line STC-1 [67,68,69]. Multiple groups tried to demonstrate the implication from in vitro experiments in animal models [70,71] and clinical studies [72,73]; however, most of them failed to lead to any meaningful results. For example, consumption or intragastric infusion of artificial sweeteners rather than natural sugars did not reach to increase the significant level of incretin hormones of EECs [70,71,72,73].
Recent single-cell RNA transcriptomic experiments have also cast doubt on the above EEC sweet taste receptor hypothesis. Multiple single-cell RNA sequencing experiments on whole intestinal epithelial cells indicated that, although Tas1r3 is expressed, its expression seems to be restricted to the tuft cells rather than the EECs [43]. In contrast, after sorting CCK-GFP-labeled cells and subjecting them to qRT-PCR at the single-cell level, roughly 20% of CCK-positive cells express significant levels of Tas1r3 but not Tas1r2 [74]. Given that intestinal tuft cells and EECs arise from common secretory cell progenitors [41,75], this discrepancy may be due to the early expression of CCK in undifferentiated cells exhibiting an expression profile somewhere between intestinal tuft cells and EECs. Independent studies using in vivo nerve imaging revealed that gut-infused sugars are detected by sodium-glucose cotransporter 1 (SGLT1) rather than Tas1r3 [74,76]. Instead, Tas1r3 only mediates cellular responses to artificial non-nutritive sweeteners, indicating a distinct role for sweet taste receptors in distinguishing tastants rather than nutrients [74].

3.2.2. Pancreatic β-Cells

Pancreatic β-cells regulate systemic glucose levels by secreting insulin. Although pancreatic β-cells must obviously be able to detect changes in circulating glucose, pancreatic β-cells also release insulin in response to other nutrients such as fructose, as well as to artificial sweeteners such as saccharine [77]. Fructose evokes Ca2+ responses and insulin release in mouse pancreatic islets. Injections of mice with fructose induce or potentiate insulin secretion when paired with or without glucose, respectively. Interestingly, all these phenomena are abolished with genetic ablation of Tas1r2 or Tas1r3. Similarly, both pharmacologic inhibition of PLC signaling and genetic ablation of TRPM5 were found to impair fructose-induced insulin secretion, demonstrating the involvement of canonical sweet taste receptor signaling.
Nakagawa et al. reported the expression of sweet taste receptors in pancreatic β-cells and investigated their intracellular responses in detail [78]. Using mouse pancreatic islets, which included β-cells, as well as the glucose-responsive β-cell line MIN6, they found that sucralose induces an immediate and sustained elevation of cytoplasmic Ca2+ and cAMP simultaneously. The sweet taste receptors expressed in pancreatic β-cells seem to couple to a distinct signaling system that activates both the Ca2+ and cAMP second messenger systems. Since pharmacologic agents that increase cAMP production in β-cells would theoretically protect these cells from various stresses and from apoptosis, sweet taste receptors are potential targets in the hunt for novel diabetes treatments.

3.2.3. Brain

The brain must not only process sensory information derived from peripheral sensory organs regarding nutrients, but it must also have mechanisms for responding to circulating nutrient levels to help it maintain systemic homeostasis. Glucose-sensing neurons in the brain are the most well-studied example. While some glucose-responsive neurons are excited by glucose, some are inhibited. Although the major molecular components for glucose detection in glucose-sensing neurons are similar to those in pancreatic β-cells [79], some glucose-sensing neurons also express sweet taste receptors [80]. This possibility was raised initially after a physiologic analysis of hypothalamic glucose-sensitive neurons. When the artificial sweetener sucralose was applied to ex vivo hypothalamic sections, specific hypothalamic neurons were activated. Pharmacologic inhibition of sweet taste receptors with the Tas1r3-specific antagonist gurmarin [80] alleviated these sucralose-induced responses, implying a role for sweet taste receptors in this phenomenon. Although RT-PCR experiments have also supported the brain expression of sweet taste receptors, the specific cell types responsible remain unknown. Recently, our own group generated Tas1r2-Cre mice and used them to demonstrate the expression of Tas1r2 across the brain in various regions [81]. Consistent with previous physiologic data [80], we observed Tas1r2 expression in the hypothalamic proopiomelanocortin (POMC)-expressing neurons whose activity indicates energy excess across the body. Interestingly, we also found Tas1r2 expression in the agout-related peptide (AgRP)-expressing neurons that oppose the function of the POMC neurons and whose activity indicates energy depletion across the body [81]. In addition to these hypothalamic neurons, we unexpectedly found expression of Tas1r2 across the entire brain. Tas1r2 expression was particularly high in the neuronal and non-neuronal cell populations comprising the circumventricular organs, such as the organum vasculosum lamina terminalis, the subfornical organ, the subcommisural organ, the median eminance (ME), and the area postrema. Expression in tanycytes and perivascular cells that line the wall of the third ventricle and ME, respectively, should be particularly advantageous for the simultaneous detection of various ligands in the cerebrospinal fluid (CSF) and blood. Thereby, Tas1r2 might be responsible for communication between CSF and blood in which the brain–blood barrier is loose. We also observed expression in vascular structures of the striatum and cerebral cortex [81]. Similarly, expression of other taste receptors such as Tas1r3, the binding partner of Tas1r2, and Tas2rs was detected in several brain areas, but the exact cell type expressing them was not mapped in detail [82,83]. Future studies will be necessary to clarify the roles these taste receptors play in the regulation of brain function.

3.2.4. Urinary Bladder

In addition to the urinary tuft cells discussed earlier [51], there are other cellular components of the urinary tract that express taste receptors [84]. Umbrella cells, which reside in the most superficial urothelial layer, express Tas1r2 and Tas1r3 in both humans and rodents. Artificial sweeteners such as saccharin increased rat bladder smooth muscle contraction in strips of bladder tissue in response to electrical field stimulation only when the strip included the urothelium. In contrast to sweet taste receptors [84], the detrusor smooth muscle (DSM) expresses bitter taste receptors [85]. The bitter-tasting compound chloroquine (CLQ) induced a concentration-dependent relaxation of carbachol- and KCl-induced contractions in human DSM strips. Furthermore, higher concentrations of CLQ significantly inhibited spontaneous and electrical field stimulation-induced contraction. Different bitter compounds such as denatonium and quinine behaved similarly to CLQ. Taste receptor agonists have thus been suggested as candidate treatments for overactive bladder [85]. The exact mechanism underlying this phenomenon, however, should be investigated further. It remains unclear whether the pharmacologic effects of tastants on the relaxation of urinary smooth muscle originate in urethral tuft cells, umbrella cells, or in the detrusor smooth muscle itself.

3.2.5. Heart

The subunits for the umami receptors showed some expression in cardiac fibroblasts, while more bitter taste receptor expression was found in cardiomyocytes [86]. Interestingly, there was some plasticity observed in these expression levels. For example, the expression of these receptors was developmentally regulated in the postnatal period. Moreover, under nutrient deprivation, several bitter taste receptors were found to be up-regulated both in vivo and in vitro. Although the details remain unclear, it does seem taste receptors have some physiologic relevance as metabolite/nutrient sensors in the heart.
The same research group also tried screening for bitter ligands capable of modifying cardiac function via bitter taste receptors expressed in cardiac tissue [87]. Using an in vitro Ca2+ mobilization assay on cells individually transfected with five bitter taste receptors cloned from rat heart, they tested 12 candidate bitter compounds from a panel of 102 natural and synthetic bitter compounds. In the Langendorff perfused-heart experiments, two representative bitter compounds, sodium thiocyanate for Tas2r108 and sodium benzoate for Tas2r137, exhibited concentration-dependent cardiac effects. Sodium thiocyanate and sodium benzoate led to a 40% decrease in left ventricular developed pressure and an increase in aortic pressure, respectively. Changes in cardiac function induced by bitter compounds were inhibited by the Gαι inhibitor pertussis toxin or the Gβγ inhibitor gallein, implicating G-protein signaling. Consistent with these results, independent research groups also found that the bitter compound denatonium similarly reduced cardiac contractility [87].

3.2.6. Respiratory Smooth Muscle

Pan-GPCR screening in human airway smooth muscles revealed abundant expression of several bitter taste receptors compared to the also prominent expression of β-adrenoreceptor ADRB2 [88]. Bitter compounds induced intracellular Ca2+ responses that were dependent on Gβγ, PLCβ, and IP3 receptor signaling. Compared to isoproterenol, which is the β-adrenergic agonist and the current gold standard drug for bronchoconstriction, bitter compounds showed more superior potency in evoking relaxation of airway smooth muscle in vitro and tracheal tension in vivo [88,89,90]. Finally, bitter compounds administered in an aerosol form alleviated the asthmatic symptoms of mouse models for allergic airway inflammation and bronchial hyperresponsiveness. The same group performed a follow-up study that used siRNA knockdown in airway smooth muscle cells to clarify that the signaling pathway responsible for this phenomenon required Gai2 rather than GNAT3 [91]. However, other groups also demonstrated the roles of the canonical taste receptor signaling pathway in alleviating L-type Ca2+ channel, which mediates bronchoconstriction [92]. Despite the contradictory explanation for the mechanism [91,92], powerful potency recapitulated by independent research groups and anatomical location of bronchus easy to administer imply the feasibility of therapeutic potentials of taste receptors and their ligands.

3.2.7. Vascular Smooth Muscle

Like bronchial smooth muscle, vascular smooth muscle also expresses several bitter taste receptors [93]. Their expression levels are similar to that of the α1A adrenoceptor, which is critical for the contraction of smooth muscle. Bitter tastant application induced muscle relaxation in a manner antagonistic to the α1A adrenoceptor. This relaxation-inducing action of bitter tastants on smooth muscle was found to be independent of the endothelium, indicating a cell-autonomous role for the bitter taste receptors in smooth muscle cells.

3.2.8. Respiratory Ciliated Cells

In the airway epithelium, most epithelial cells are ciliated. Motile cilia beat together to move luminal irritants out of the airway. This beating of these motile cilia is regulated by taste receptor signaling [94]. Single ciliated epithelial cells in the human airway were found via immunostaining with specific antibodies to express multiple bitter taste receptors. Interestingly, the subcellular localizations of the different receptors were distinguishable from one another, with TAS2R4 and TAS2R38 localizing near the ciliary tip and TAS2R43 and TAS2R46 localizing to the ciliary base. Application of several different bitter compounds not only elicited intracellular Ca2+ responses but also accelerated ciliary beat frequency via nitric oxide (NO) synthesis. In more recent scRNA-seq data [47,48], however, taste receptors and their downstream effectors were only observed in airway tuft cells. This means that there seems to be a discrepancy between the expression of bitter taste receptors at the RNA and protein levels.

3.2.9. Immune Cells

In the purified human blood cells, chemosensory receptors showed cell type-specific expression patterns [95]. For example, most ORs were strongly biased in B cells, T cells, and polymorphonuclear neutrophils (PMNs), while a few specific ORs were detected in monocytes and natural killer (NK) cells. Compared to ORs, taste receptors showed weakly biased expression patterns. Using antibodies against ORs and taste receptors, fluorescent-associated cell sorting and immunocytochemistry revealed that chemosensory receptors are co-expressed in the subpopulations of dedicated cell types. Exposure to either sweet or bitter tastant induced PMNs migration, which was blocked by Gi inhibitor, or gustducin knockdown, indicating the functional expression of taste receptors in PMNs.
Given that polymorphism of TAS2R38 is associated with multiple immune-related diseases [96,97,98,99], TAS2R38 in immune cells has been paid attention to. TAS2R38 was higher expressed in CD3+ T cells than CD19+ B cells and in CD4+ T cells than in CD8+ T cells [100]. As T cells become mature, TAS2R38 expression increases. Application of goitrin, TAS2R38 activator, induced calcium flux in T cells and tumor necrosis factor- α (TNF-α). According to the polymorphism type of TAS2R38, the response of T cells to goitrin differed, implying the functional contribution of TAS2R38 in T cells. Later, other groups also agreed with TAS2R38 expression in lymphocytes, which were infiltrated in AD skin, but they argued against the roles of TAS2R38 in lymphocytes [101]. Activation of TAS2R38 with agonists rather inhibited cell migration and unexpectedly suppressed TNF-α production regardless of TAS2R38, which implies the off-target effect of the chemicals.
In macrophages, the signal transduction mechanism of bitter taste receptors was more extensively investigated [102]. Fluorescent imaging to measure the intracellular secondary messengers and pharmacologic manipulation revealed a sequential signaling cascade induced by the activation of bitter taste receptors with bitter tastants or microbe-derived LasI, which increases intracellular Ca2+ and produces NO and cyclic guanosine monophosphate (cGMP). Independently, downregulation of the cAMP level was also observed, but it is irrelevant to NO and cGMP signaling. Finally, both pathways resulted in the phagocytosis of macrophages. Furthermore, in vitro co-culture of macrophage and H441 cells, the airway cell lines, recapitulated the cross-reactivity of macrophage to NO diffused from upper airway ciliated cells, facilitating phagocytosis.
As immune cells communicate with various types of cells via cytokines, the effects of taste receptors in immune cells should be considered systemically together with those of taste receptors in the communicating partner cells.

3.2.10. Adipose Tissue

Adipocytes also express taste receptors, but their roles in adipogenesis remain controversial [103,104]. Genetic loss of taste-related genes, such as Tas1r2, Tas1r3, or GNAT3, was found to reduce adipose tissue size when mice were fed a high-fat diet [105,106]. Both murine and human adipocytes express the taste receptors Tas1r2, Tas1r3, and TAS2R38. In vitro application of artificial sweeteners or bitter tastants was found to affect the differentiation of 3T3-L1 cells and embryonic mesenchymal stem cells into mature adipocytes [103,104,106]. 3T3-L1 cells treated with tastants exhibited increases in intracellular Ca2+ and cAMP [104], as well as activation of the Akt-ERT1/2 pathways [103]. This led to the differentiation of preadipocyte-like cells into mature adipocytes. Based on the above evidence, one group concluded that taste receptors in preadipocytes are crucial in the regulation of adipogenesis. Other groups, however, reported that Tas1r2 and Tas1r3 double KO mutants showed comparable levels of tastant-induced adipogenesis and Akt phosphorylation, suggesting that these two receptors at least are dispensable [103]. This means that just because cells exhibit ectopic taste receptor expression does not always mean those taste receptors play a significant role in the physiology of those cells. We must also consider the possibility that tastants activate some unknown off-target receptor rather than the taste receptors themselves.

4. Conclusions

Here, we have summarized the literature regarding the ectopic expression of taste receptors (Table 1). Ectopic taste receptors are largely involved in three biological processes. First, taste receptors can help regulate metabolism via their ability to detect circulating nutrients and exogenous compounds. This is the function of the intestinal EECs, pancreatic β-cells, and hypothalamic neurons. Second, upon exposure to microbe-derived compounds, taste receptors expressed in tuft cells can trigger immune responses in communication with immune cells via the ILC-2 circuit. Last, taste receptors help tune involuntary muscle tone.
How are ectopic taste receptors activated? Tuft cells are exposed to the lumen of the digestive and respiratory tracts, giving them direct access to taste receptor ligands. If the ectopic taste receptors are localized deep within a particular tissue, however, the physicochemical and pharmacokinetic properties of each exogenous compound would determine whether it can act as a ligand for ectopic taste receptors in vivo. Alternatively, ectopic taste receptors deep in the tissues may also respond to unknown endogenous ligands.
Conventional tastants are recognized not only by taste receptors but also by off-target receptors. As most of the studies of the function of ectopic taste receptors have relied on the pharmacologic application of tastants in vitro and in vivo, it can be easy to misattribute observed effects to a contribution of the ectopic taste receptors themselves. Therefore, genetic approaches should always accompany pharmacologic approaches to validate the functions of ectopic taste receptors. We do expect, however, that further investigations will confirm at least some of the perceived therapeutic potential of taste receptors and their ligands.

Author Contributions

Conceptualization, S.Y.K. and Y.T.J.; writing—original draft preparation, S.Y.K. and Y.T.J.; writing—review and editing, S.Y.K. and Y.T.J.; funding acquisition, Y.T.J. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by grants from the National Research Foundation of Korea (NRF-2019R1C1C1006751 and NRF-2020R1A4A3078962), by a Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korean Government (the Ministry of Science and ICT, the Ministry of Health and Welfare; 21C0712L1), and by a grant from Korea University (K2117151).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Matsunami, H.; Montmayeur, J.P.; Buck, L.B. A family of candidate taste receptors in human and mouse. Nature 2000, 404, 601–604. [Google Scholar] [CrossRef] [PubMed]
  2. Hoon, M.A.; Adler, E.; Lindemeier, J.; Battey, J.F.; Ryba, N.J.; Zuker, C.S. Putative mammalian taste receptors: A class of taste-specific GPCRs with distinct topographic selectivity. Cell 1999, 96, 541–551. [Google Scholar] [CrossRef]
  3. Dulac, C.; Axel, R. A novel family of genes encoding putative pheromone receptors in mammals. Cell 1995, 83, 195–206. [Google Scholar] [CrossRef]
  4. Buck, L.; Axel, R. A novel multigene family may encode odorant receptors: A molecular basis for odor recognition. Cell 1991, 65, 175–187. [Google Scholar] [CrossRef]
  5. Adler, E.; Hoon, M.A.; Mueller, K.L.; Chandrashekar, J.; Ryba, N.J.; Zuker, C.S. A novel family of mammalian taste receptors. Cell 2000, 100, 693–702. [Google Scholar] [CrossRef]
  6. Max, M.; Shanker, Y.G.; Huang, L.; Rong, M.; Liu, Z.; Campagne, F.; Weinstein, H.; Damak, S.; Margolskee, R.F. Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac. Nat. Genet. 2001, 28, 58–63. [Google Scholar] [CrossRef]
  7. Montmayeur, J.P.; Liberles, S.D.; Matsunami, H.; Buck, L.B. A candidate taste receptor gene near a sweet taste locus. Nat. Neurosci. 2001, 4, 492–498. [Google Scholar] [CrossRef]
  8. Kitagawa, M.; Kusakabe, Y.; Miura, H.; Ninomiya, Y.; Hino, A. Molecular genetic identification of a candidate receptor gene for sweet taste. Biochem. Biophys. Res. Commun. 2001, 283, 236–242. [Google Scholar] [CrossRef]
  9. Sainz, E.; Korley, J.N.; Battey, J.F.; Sullivan, S.L. Identification of a novel member of the T1R family of putative taste receptors. J. Neurochem. 2001, 77, 896–903. [Google Scholar] [CrossRef]
  10. Capeless, C.G.; Whitney, G. The genetic basis of preference for sweet substances among inbred strains of mice: Preference ratio phenotypes and the alleles of the Sac and dpa loci. Chem. Senses 1995, 20, 291–298. [Google Scholar] [CrossRef]
  11. Lush, I.E. The genetics of tasting in mice. VI. Saccharin, acesulfame, dulcin and sucrose. Genet. Res. 1989, 53, 95–99. [Google Scholar] [CrossRef] [PubMed]
  12. Nelson, G.; Hoon, M.A.; Chandrashekar, J.; Zhang, Y.; Ryba, N.J.; Zuker, C.S. Mammalian sweet taste receptors. Cell 2001, 106, 381–390. [Google Scholar] [CrossRef]
  13. Zhao, G.Q.; Zhang, Y.; Hoon, M.A.; Chandrashekar, J.; Erlenbach, I.; Ryba, N.J.; Zuker, C.S. The receptors for mammalian sweet and umami taste. Cell 2003, 115, 255–266. [Google Scholar] [CrossRef]
  14. Chandrashekar, J.; Mueller, K.L.; Hoon, M.A.; Adler, E.; Feng, L.; Guo, W.; Zuker, C.S.; Ryba, N.J. T2Rs function as bitter taste receptors. Cell 2000, 100, 703–711. [Google Scholar] [CrossRef]
  15. Mueller, K.L.; Hoon, M.A.; Erlenbach, I.; Chandrashekar, J.; Zuker, C.S.; Ryba, N.J. The receptors and coding logic for bitter taste. Nature 2005, 434, 225–229. [Google Scholar] [CrossRef]
  16. Ogura, T.; Mackay-Sim, A.; Kinnamon, S.C. Bitter taste transduction of denatonium in the mudpuppy Necturus maculosus. J. Neurosci. 1997, 17, 3580–3587. [Google Scholar] [CrossRef]
  17. Striem, B.J.; Pace, U.; Zehavi, U.; Naim, M.; Lancet, D. Sweet tastants stimulate adenylate cyclase coupled to GTP-binding protein in rat tongue membranes. Biochem. J. 1989, 260, 121–126. [Google Scholar] [CrossRef]
  18. Wong, G.T.; Gannon, K.S.; Margolskee, R.F. Transduction of bitter and sweet taste by gustducin. Nature 1996, 381, 796–800. [Google Scholar] [CrossRef]
  19. Rossler, P.; Boekhoff, I.; Tareilus, E.; Beck, S.; Breer, H.; Freitag, J. G protein betagamma complexes in circumvallate taste cells involved in bitter transduction. Chem. Senses 2000, 25, 413–421. [Google Scholar] [CrossRef]
  20. Huang, L.; Shanker, Y.G.; Dubauskaite, J.; Zheng, J.Z.; Yan, W.; Rosenzweig, S.; Spielman, A.I.; Max, M.; Margolskee, R.F. Ggamma13 colocalizes with gustducin in taste receptor cells and mediates IP3 responses to bitter denatonium. Nat. Neurosci. 1999, 2, 1055–1062. [Google Scholar] [CrossRef]
  21. Zhang, Y.; Hoon, M.A.; Chandrashekar, J.; Mueller, K.L.; Cook, B.; Wu, D.; Zuker, C.S.; Ryba, N.J. Coding of sweet, bitter, and umami tastes: Different receptor cells sharing similar signaling pathways. Cell 2003, 112, 293–301. [Google Scholar] [CrossRef]
  22. McLaughlin, S.K.; McKinnon, P.J.; Margolskee, R.F. Gustducin is a taste-cell-specific G protein closely related to the transducins. Nature 1992, 357, 563–569. [Google Scholar] [CrossRef] [PubMed]
  23. Ruiz-Avila, L.; Wong, G.T.; Damak, S.; Margolskee, R.F. Dominant loss of responsiveness to sweet and bitter compounds caused by a single mutation in alpha -gustducin. Proc. Natl. Acad. Sci. USA 2001, 98, 8868–8873. [Google Scholar] [CrossRef]
  24. Perez, C.A.; Huang, L.; Rong, M.; Kozak, J.A.; Preuss, A.K.; Zhang, H.; Max, M.; Margolskee, R.F. A transient receptor potential channel expressed in taste receptor cells. Nat. Neurosci. 2002, 5, 1169–1176. [Google Scholar] [CrossRef] [PubMed]
  25. Hisatsune, C.; Yasumatsu, K.; Takahashi-Iwanaga, H.; Ogawa, N.; Kuroda, Y.; Yoshida, R.; Ninomiya, Y.; Mikoshiba, K. Abnormal taste perception in mice lacking the type 3 inositol 1,4,5-trisphosphate receptor. J. Biol. Chem. 2007, 282, 37225–37231. [Google Scholar] [CrossRef]
  26. Ruiz-Avila, L.; McLaughlin, S.K.; Wildman, D.; McKinnon, P.J.; Robichon, A.; Spickofsky, N.; Margolskee, R.F. Coupling of bitter receptor to phosphodiesterase through transducin in taste receptor cells. Nature 1995, 376, 80–85. [Google Scholar] [CrossRef]
  27. Avenet, P.; Hofmann, F.; Lindemann, B. Transduction in taste receptor cells requires cAMP-dependent protein kinase. Nature 1988, 331, 351–354. [Google Scholar] [CrossRef]
  28. Clapp, T.R.; Trubey, K.R.; Vandenbeuch, A.; Stone, L.M.; Margolskee, R.F.; Chaudhari, N.; Kinnamon, S.C. Tonic activity of Galpha-gustducin regulates taste cell responsivity. FEBS Lett. 2008, 582, 3783–3787. [Google Scholar] [CrossRef]
  29. Prawitt, D.; Monteilh-Zoller, M.K.; Brixel, L.; Spangenberg, C.; Zabel, B.; Fleig, A.; Penner, R. TRPM5 is a transient Ca2+-activated cation channel responding to rapid changes in [Ca2+]i. Proc. Natl. Acad. Sci. USA 2003, 100, 15166–15171. [Google Scholar] [CrossRef]
  30. Liu, D.; Liman, E.R. Intracellular Ca2+ and the phospholipid PIP2 regulate the taste transduction ion channel TRPM5. Proc. Natl. Acad. Sci. USA 2003, 100, 15160–15165. [Google Scholar] [CrossRef] [Green Version]
  31. Zhang, Z.; Zhao, Z.; Margolskee, R.; Liman, E. The transduction channel TRPM5 is gated by intracellular calcium in taste cells. J. Neurosci. 2007, 27, 5777–5786. [Google Scholar] [CrossRef] [PubMed]
  32. Hofmann, T.; Chubanov, V.; Gudermann, T.; Montell, C. TRPM5 is a voltage-modulated and Ca(2+)-activated monovalent selective cation channel. Curr. Biol. 2003, 13, 1153–1158. [Google Scholar] [CrossRef]
  33. Yoshida, R.; Sanematsu, K.; Shigemura, N.; Yasumatsu, K.; Ninomiya, Y. Taste receptor cells responding with action potentials to taste stimuli and their molecular expression of taste related genes. Chem. Senses 2005, 30 (Suppl. 1), i19–i20. [Google Scholar] [CrossRef] [PubMed]
  34. Taruno, A.; Vingtdeux, V.; Ohmoto, M.; Ma, Z.; Dvoryanchikov, G.; Li, A.; Adrien, L.; Zhao, H.; Leung, S.; Abernethy, M.; et al. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature 2013, 495, 223–226. [Google Scholar] [CrossRef] [PubMed]
  35. Ma, Z.; Taruno, A.; Ohmoto, M.; Jyotaki, M.; Lim, J.C.; Miyazaki, H.; Niisato, N.; Marunaka, Y.; Lee, R.J.; Hoff, H.; et al. CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. Neuron 2018, 98, 547–561.e10. [Google Scholar] [CrossRef] [PubMed]
  36. Finger, T.E.; Danilova, V.; Barrows, J.; Bartel, D.L.; Vigers, A.J.; Stone, L.; Hellekant, G.; Kinnamon, S.C. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 2005, 310, 1495–1499. [Google Scholar] [CrossRef]
  37. Eddy, M.C.; Eschle, B.K.; Barrows, J.; Hallock, R.M.; Finger, T.E.; Delay, E.R. Double P2X2/P2X3 purinergic receptor knockout mice do not taste NaCl or the artificial sweetener SC45647. Chem. Senses 2009, 34, 789–797. [Google Scholar] [CrossRef]
  38. O’Leary, C.E.; Schneider, C.; Locksley, R.M. Tuft Cells-Systemically Dispersed Sensory Epithelia Integrating Immune and Neural Circuitry. Annu. Rev. Immunol. 2019, 37, 47–72. [Google Scholar] [CrossRef]
  39. Zheng, X.; Tizzano, M.; Redding, K.; He, J.; Peng, X.; Jiang, P.; Xu, X.; Zhou, X.; Margolskee, R.F. Gingival solitary chemosensory cells are immune sentinels for periodontitis. Nat. Commun. 2019, 10, 4496. [Google Scholar] [CrossRef]
  40. Howitt, M.R.; Lavoie, S.; Michaud, M.; Blum, A.M.; Tran, S.V.; Weinstock, J.V.; Gallini, C.A.; Redding, K.; Margolskee, R.F.; Osborne, L.C.; et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 2016, 351, 1329–1333. [Google Scholar] [CrossRef] [Green Version]
  41. Gracz, A.D.; Samsa, L.A.; Fordham, M.J.; Trotier, D.C.; Zwarycz, B.; Lo, Y.H.; Bao, K.; Starmer, J.; Raab, J.R.; Shroyer, N.F.; et al. Sox4 Promotes Atoh1-Independent Intestinal Secretory Differentiation Toward Tuft and Enteroendocrine Fates. Gastroenterology 2018, 155, 1508–1523.e10. [Google Scholar] [CrossRef]
  42. Lei, W.; Ren, W.; Ohmoto, M.; Urban, J.F., Jr.; Matsumoto, I.; Margolskee, R.F.; Jiang, P. Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine. Proc. Natl. Acad. Sci. USA 2018, 115, 5552–5557. [Google Scholar] [CrossRef] [PubMed]
  43. Haber, A.L.; Biton, M.; Rogel, N.; Herbst, R.H.; Shekhar, K.; Smillie, C.; Burgin, G.; Delorey, T.M.; Howitt, M.R.; Katz, Y.; et al. A single-cell survey of the small intestinal epithelium. Nature 2017, 551, 333–339. [Google Scholar] [CrossRef]
  44. Schneider, C.; O’Leary, C.E.; von Moltke, J.; Liang, H.E.; Ang, Q.Y.; Turnbaugh, P.J.; Radhakrishnan, S.; Pellizzon, M.; Ma, A.; Locksley, R.M. A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling. Cell 2018, 174, 271–284.e14. [Google Scholar] [CrossRef] [PubMed]
  45. Lee, R.J.; Kofonow, J.M.; Rosen, P.L.; Siebert, A.P.; Chen, B.; Doghramji, L.; Xiong, G.; Adappa, N.D.; Palmer, J.N.; Kennedy, D.W.; et al. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J. Clin. Investig. 2014, 124, 1393–1405. [Google Scholar] [CrossRef]
  46. Saunders, C.J.; Christensen, M.; Finger, T.E.; Tizzano, M. Cholinergic neurotransmission links solitary chemosensory cells to nasal inflammation. Proc. Natl. Acad. Sci. USA 2014, 111, 6075–6080. [Google Scholar] [CrossRef] [PubMed]
  47. Montoro, D.T.; Haber, A.L.; Biton, M.; Vinarsky, V.; Lin, B.; Birket, S.E.; Yuan, F.; Chen, S.; Leung, H.M.; Villoria, J.; et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 2018, 560, 319–324. [Google Scholar] [CrossRef] [PubMed]
  48. Plasschaert, L.W.; Zilionis, R.; Choo-Wing, R.; Savova, V.; Knehr, J.; Roma, G.; Klein, A.M.; Jaffe, A.B. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature 2018, 560, 377–381. [Google Scholar] [CrossRef]
  49. Miller, C.N.; Proekt, I.; von Moltke, J.; Wells, K.L.; Rajpurkar, A.R.; Wang, H.; Rattay, K.; Khan, I.S.; Metzger, T.C.; Pollack, J.L.; et al. Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature 2018, 559, 627–631. [Google Scholar] [CrossRef]
  50. Bornstein, C.; Nevo, S.; Giladi, A.; Kadouri, N.; Pouzolles, M.; Gerbe, F.; David, E.; Machado, A.; Chuprin, A.; Toth, B.; et al. Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells. Nature 2018, 559, 622–626. [Google Scholar] [CrossRef]
  51. Deckmann, K.; Filipski, K.; Krasteva-Christ, G.; Fronius, M.; Althaus, M.; Rafiq, A.; Papadakis, T.; Renno, L.; Jurastow, I.; Wessels, L.; et al. Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes. Proc. Natl. Acad. Sci. USA 2014, 111, 8287–8292. [Google Scholar] [CrossRef] [PubMed]
  52. Hollenhorst, M.I.; Nandigama, R.; Evers, S.B.; Gamayun, I.; Abdel Wadood, N.; Salah, A.; Pieper, M.; Wyatt, A.; Stukalov, A.; Gebhardt, A.; et al. Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection. J. Clin. Investig. 2022, 132. [Google Scholar] [CrossRef] [PubMed]
  53. Tizzano, M.; Gulbransen, B.D.; Vandenbeuch, A.; Clapp, T.R.; Herman, J.P.; Sibhatu, H.M.; Churchill, M.E.; Silver, W.L.; Kinnamon, S.C.; Finger, T.E. Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc. Natl. Acad. Sci. USA 2010, 107, 3210–3215. [Google Scholar] [CrossRef]
  54. Tizzano, M.; Cristofoletti, M.; Sbarbati, A.; Finger, T.E. Expression of taste receptors in solitary chemosensory cells of rodent airways. BMC Pulm. Med. 2011, 11, 3. [Google Scholar] [CrossRef]
  55. Xiong, Z.; Zhu, X.; Geng, J.; Xu, Y.; Wu, R.; Li, C.; Fan, D.; Qin, X.; Du, Y.; Tian, Y.; et al. Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine. Immunity 2022, 55, 686–700. [Google Scholar] [CrossRef] [PubMed]
  56. Yamashita, J.; Ohmoto, M.; Yamaguchi, T.; Matsumoto, I.; Hirota, J. Skn-1a/Pou2f3 functions as a master regulator to generate Trpm5-expressing chemosensory cells in mice. PLoS ONE 2017, 12, e0189340. [Google Scholar] [CrossRef]
  57. Matsumoto, I.; Ohmoto, M.; Narukawa, M.; Yoshihara, Y.; Abe, K. Skn-1a (Pou2f3) specifies taste receptor cell lineage. Nat. Neurosci. 2011, 14, 685–687. [Google Scholar] [CrossRef]
  58. Gerbe, F.; Sidot, E.; Smyth, D.J.; Ohmoto, M.; Matsumoto, I.; Dardalhon, V.; Cesses, P.; Garnier, L.; Pouzolles, M.; Brulin, B.; et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 2016, 529, 226–230. [Google Scholar] [CrossRef]
  59. Luo, X.C.; Chen, Z.H.; Xue, J.B.; Zhao, D.X.; Lu, C.; Li, Y.H.; Li, S.M.; Du, Y.W.; Liu, Q.; Wang, P.; et al. Infection by the parasitic helminth Trichinella spiralis activates a Tas2r-mediated signaling pathway in intestinal tuft cells. Proc. Natl. Acad. Sci. USA 2019, 116, 5564–5569. [Google Scholar] [CrossRef]
  60. Liu, S.; Lu, S.; Xu, R.; Atzberger, A.; Gunther, S.; Wettschureck, N.; Offermanns, S. Members of Bitter Taste Receptor Cluster Tas2r143/Tas2r135/Tas2r126 Are Expressed in the Epithelium of Murine Airways and Other Non-gustatory Tissues. Front. Physiol. 2017, 8, 849. [Google Scholar] [CrossRef] [Green Version]
  61. Howitt, M.R.; Cao, Y.G.; Gologorsky, M.B.; Li, J.A.; Haber, A.L.; Biton, M.; Lang, J.; Michaud, M.; Regev, A.; Garrett, W.S. The Taste Receptor TAS1R3 Regulates Small Intestinal Tuft Cell Homeostasis. Immunohorizons 2020, 4, 23–32. [Google Scholar] [CrossRef]
  62. Jeruzal-Swiatecka, J.; Borkowska, E.; Laszczych, M.; Nowicka, Z.; Pietruszewska, W. TAS2R38 Bitter Taste Receptor Expression in Chronic Rhinosinusitis with Nasal Polyps: New Data on Polypoid Tissue. Int. J. Mol. Sci. 2022, 23, 7345. [Google Scholar] [CrossRef] [PubMed]
  63. Goto, N.; Fukuda, A.; Yamaga, Y.; Yoshikawa, T.; Maruno, T.; Maekawa, H.; Inamoto, S.; Kawada, K.; Sakai, Y.; Miyoshi, H.; et al. Lineage tracing and targeting of IL17RB(+) tuft cell-like human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 2019, 116, 12996–13005. [Google Scholar] [CrossRef]
  64. Baine, M.K.; Hsieh, M.S.; Lai, W.V.; Egger, J.V.; Jungbluth, A.A.; Daneshbod, Y.; Beras, A.; Spencer, R.; Lopardo, J.; Bodd, F.; et al. SCLC Subtypes Defined by ASCL1, NEUROD1, POU2F3, and YAP1: A Comprehensive Immunohistochemical and Histopathologic Characterization. J. Thorac. Oncol. 2020, 15, 1823–1835. [Google Scholar] [CrossRef]
  65. Furness, J.B.; Rivera, L.R.; Cho, H.J.; Bravo, D.M.; Callaghan, B. The gut as a sensory organ. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 729–740. [Google Scholar] [CrossRef] [PubMed]
  66. Bezencon, C.; le Coutre, J.; Damak, S. Taste-signaling proteins are coexpressed in solitary intestinal epithelial cells. Chem. Senses 2007, 32, 41–49. [Google Scholar] [CrossRef] [PubMed]
  67. Dyer, J.; Salmon, K.S.; Zibrik, L.; Shirazi-Beechey, S.P. Expression of sweet taste receptors of the T1R family in the intestinal tract and enteroendocrine cells. Biochem. Soc. Trans. 2005, 33, 302–305. [Google Scholar] [CrossRef]
  68. Jang, H.J.; Kokrashvili, Z.; Theodorakis, M.J.; Carlson, O.D.; Kim, B.J.; Zhou, J.; Kim, H.H.; Xu, X.; Chan, S.L.; Juhaszova, M.; et al. Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc. Natl. Acad. Sci. USA 2007, 104, 15069–15074. [Google Scholar] [CrossRef]
  69. Kokrashvili, Z.; Mosinger, B.; Margolskee, R.F. T1r3 and alpha-gustducin in gut regulate secretion of glucagon-like peptide-1. Ann. N. Y. Acad. Sci. 2009, 1170, 91–94. [Google Scholar] [CrossRef]
  70. Fujita, Y.; Wideman, R.D.; Speck, M.; Asadi, A.; King, D.S.; Webber, T.D.; Haneda, M.; Kieffer, T.J. Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo. Am. J. Physiol. Endocrinol. Metab. 2009, 296, E473–E479. [Google Scholar] [CrossRef] [Green Version]
  71. Glendinning, J.I.; Hart, S.; Lee, H.; Maleh, J.; Ortiz, G.; Ryu, Y.S.; Sanchez, A.; Shelling, S.; Williams, N. Low-calorie sweeteners cause only limited metabolic effects in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2020, 318, R70–R80. [Google Scholar] [CrossRef] [PubMed]
  72. Steinert, R.E.; Frey, F.; Topfer, A.; Drewe, J.; Beglinger, C. Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides. Br. J. Nutr. 2011, 105, 1320–1328. [Google Scholar] [CrossRef] [PubMed]
  73. Ford, H.E.; Peters, V.; Martin, N.M.; Sleeth, M.L.; Ghatei, M.A.; Frost, G.S.; Bloom, S.R. Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal-weight subjects. Eur. J. Clin. Nutr. 2011, 65, 508–513. [Google Scholar] [CrossRef]
  74. Buchanan, K.L.; Rupprecht, L.E.; Kaelberer, M.M.; Sahasrabudhe, A.; Klein, M.E.; Villalobos, J.A.; Liu, W.W.; Yang, A.; Gelman, J.; Park, S.; et al. The preference for sugar over sweetener depends on a gut sensor cell. Nat. Neurosci. 2022, 25, 191–200. [Google Scholar] [CrossRef]
  75. Beumer, J.; Clevers, H. Cell fate specification and differentiation in the adult mammalian intestine. Nat. Rev. Mol. Cell Biol. 2021, 22, 39–53. [Google Scholar] [CrossRef] [PubMed]
  76. Tan, H.E.; Sisti, A.C.; Jin, H.; Vignovich, M.; Villavicencio, M.; Tsang, K.S.; Goffer, Y.; Zuker, C.S. The gut-brain axis mediates sugar preference. Nature 2020, 580, 511–516. [Google Scholar] [CrossRef] [PubMed]
  77. Kyriazis, G.A.; Soundarapandian, M.M.; Tyrberg, B. Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion. Proc. Natl. Acad. Sci. USA 2012, 109, E524–E532. [Google Scholar] [CrossRef]
  78. Nakagawa, Y.; Nagasawa, M.; Yamada, S.; Hara, A.; Mogami, H.; Nikolaev, V.O.; Lohse, M.J.; Shigemura, N.; Ninomiya, Y.; Kojima, I. Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion. PLoS ONE 2009, 4, e5106. [Google Scholar] [CrossRef]
  79. Ashford, M.L.; Boden, P.R.; Treherne, J.M. Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K+ channels. Pflug. Arch. 1990, 415, 479–483. [Google Scholar] [CrossRef]
  80. Kohno, D.; Koike, M.; Ninomiya, Y.; Kojima, I.; Kitamura, T.; Yada, T. Sweet Taste Receptor Serves to Activate Glucose- and Leptin-Responsive Neurons in the Hypothalamic Arcuate Nucleus and Participates in Glucose Responsiveness. Front. Neurosci. 2016, 10, 502. [Google Scholar] [CrossRef] [Green Version]
  81. Jang, J.H.; Kim, H.K.; Seo, D.W.; Ki, S.Y.; Park, S.; Choi, S.H.; Kim, D.H.; Moon, S.J.; Jeong, Y.T. Whole-Brain Mapping of the Expression Pattern of T1R2, a Subunit Specific to the Sweet Taste Receptor. Front. Neuroanat. 2021, 15, 751839. [Google Scholar] [CrossRef] [PubMed]
  82. Singh, N.; Vrontakis, M.; Parkinson, F.; Chelikani, P. Functional bitter taste receptors are expressed in brain cells. Biochem. Biophys. Res. Commun. 2011, 406, 146–151. [Google Scholar] [CrossRef] [PubMed]
  83. Herrera Moro Chao, D.; Argmann, C.; Van Eijk, M.; Boot, R.G.; Ottenhoff, R.; Van Roomen, C.; Foppen, E.; Siljee, J.E.; Unmehopa, U.A.; Kalsbeek, A.; et al. Impact of obesity on taste receptor expression in extra-oral tissues: Emphasis on hypothalamus and brainstem. Sci. Rep. 2016, 6, 29094. [Google Scholar] [CrossRef] [PubMed]
  84. Elliott, R.A.; Kapoor, S.; Tincello, D.G. Expression and distribution of the sweet taste receptor isoforms T1R2 and T1R3 in human and rat bladders. J. Urol. 2011, 186, 2455–2462. [Google Scholar] [CrossRef] [PubMed]
  85. Zhai, K.; Yang, Z.; Zhu, X.; Nyirimigabo, E.; Mi, Y.; Wang, Y.; Liu, Q.; Man, L.; Wu, S.; Jin, J.; et al. Activation of bitter taste receptors (tas2rs) relaxes detrusor smooth muscle and suppresses overactive bladder symptoms. Oncotarget 2016, 7, 21156–21167. [Google Scholar] [CrossRef]
  86. Foster, S.R.; Porrello, E.R.; Purdue, B.; Chan, H.W.; Voigt, A.; Frenzel, S.; Hannan, R.D.; Moritz, K.M.; Simmons, D.G.; Molenaar, P.; et al. Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart. PLoS ONE 2013, 8, e64579. [Google Scholar] [CrossRef]
  87. Foster, S.R.; Blank, K.; See Hoe, L.E.; Behrens, M.; Meyerhof, W.; Peart, J.N.; Thomas, W.G. Bitter taste receptor agonists elicit G-protein-dependent negative inotropy in the murine heart. FASEB J. 2014, 28, 4497–4508. [Google Scholar] [CrossRef]
  88. Deshpande, D.A.; Wang, W.C.; McIlmoyle, E.L.; Robinett, K.S.; Schillinger, R.M.; An, S.S.; Sham, J.S.; Liggett, S.B. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat. Med. 2010, 16, 1299–1304. [Google Scholar] [CrossRef]
  89. Deshpande, D.A.; Robinett, K.S.; Wang, W.C.; Sham, J.S.; An, S.S.; Liggett, S.B. Bronchodilator activity of bitter tastants in human tissue. Nat. Med. 2011, 17, 776–778. [Google Scholar] [CrossRef]
  90. Belvisi, M.G.; Dale, N.; Birrell, M.A.; Canning, B.J. Bronchodilator activity of bitter tastants in human tissue. Nat. Med. 2011, 17, 776. [Google Scholar] [CrossRef]
  91. Kim, D.; Woo, J.A.; Geffken, E.; An, S.S.; Liggett, S.B. Coupling of Airway Smooth Muscle Bitter Taste Receptors to Intracellular Signaling and Relaxation Is via Galphai1,2,3. Am. J. Respir. Cell. Mol. Biol. 2017, 56, 762–771. [Google Scholar] [CrossRef] [PubMed]
  92. Zhang, C.H.; Lifshitz, L.M.; Uy, K.F.; Ikebe, M.; Fogarty, K.E.; ZhuGe, R. The cellular and molecular basis of bitter tastant-induced bronchodilation. PLoS Biol. 2013, 11, e1001501. [Google Scholar] [CrossRef]
  93. Manson, M.L.; Safholm, J.; Al-Ameri, M.; Bergman, P.; Orre, A.C.; Sward, K.; James, A.; Dahlen, S.E.; Adner, M. Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle. Eur. J. Pharmacol. 2014, 740, 302–311. [Google Scholar] [CrossRef]
  94. Shah, A.S.; Ben-Shahar, Y.; Moninger, T.O.; Kline, J.N.; Welsh, M.J. Motile cilia of human airway epithelia are chemosensory. Science 2009, 325, 1131–1134. [Google Scholar] [CrossRef]
  95. Malki, A.; Fiedler, J.; Fricke, K.; Ballweg, I.; Pfaffl, M.W.; Krautwurst, D. Class I odorant receptors, TAS1R and TAS2R taste receptors, are markers for subpopulations of circulating leukocytes. J. Leukoc. Biol. 2015, 97, 533–545. [Google Scholar] [CrossRef]
  96. Adappa, N.D.; Howland, T.J.; Palmer, J.N.; Kennedy, D.W.; Doghramji, L.; Lysenko, A.; Reed, D.R.; Lee, R.J.; Cohen, N.A. Genetics of the taste receptor T2R38 correlates with chronic rhinosinusitis necessitating surgical intervention. Int. Forum Allergy Rhinol. 2013, 3, 184–187. [Google Scholar] [CrossRef] [PubMed]
  97. Adappa, N.D.; Zhang, Z.; Palmer, J.N.; Kennedy, D.W.; Doghramji, L.; Lysenko, A.; Reed, D.R.; Scott, T.; Zhao, N.W.; Owens, D.; et al. The bitter taste receptor T2R38 is an independent risk factor for chronic rhinosinusitis requiring sinus surgery. Int. Forum Allergy Rhinol. 2014, 4, 3–7. [Google Scholar] [CrossRef]
  98. Adappa, N.D.; Farquhar, D.; Palmer, J.N.; Kennedy, D.W.; Doghramji, L.; Morris, S.A.; Owens, D.; Mansfield, C.; Lysenko, A.; Lee, R.J.; et al. TAS2R38 genotype predicts surgical outcome in nonpolypoid chronic rhinosinusitis. Int. Forum Allergy Rhinol. 2016, 6, 25–33. [Google Scholar] [CrossRef] [PubMed]
  99. Choi, J.H.; Lee, J.; Choi, I.J.; Kim, Y.W.; Ryu, K.W.; Kim, J. Genetic Variation in the TAS2R38 Bitter Taste Receptor and Gastric Cancer Risk in Koreans. Sci. Rep. 2016, 6, 26904. [Google Scholar] [CrossRef]
  100. Tran, H.T.T.; Herz, C.; Ruf, P.; Stetter, R.; Lamy, E. Human T2R38 Bitter Taste Receptor Expression in Resting and Activated Lymphocytes. Front. Immunol. 2018, 9, 2949. [Google Scholar] [CrossRef]
  101. Sakakibara, M.; Sumida, H.; Yanagida, K.; Miyasato, S.; Nakamura, M.; Sato, S. Bitter taste receptor T2R38 is expressed on skin-infiltrating lymphocytes and regulates lymphocyte migration. Sci. Rep. 2022, 12, 11790. [Google Scholar] [CrossRef] [PubMed]
  102. Gopallawa, I.; Freund, J.R.; Lee, R.J. Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling. Cell Mol. Life Sci. 2021, 78, 271–286. [Google Scholar] [CrossRef] [PubMed]
  103. Simon, B.R.; Parlee, S.D.; Learman, B.S.; Mori, H.; Scheller, E.L.; Cawthorn, W.P.; Ning, X.; Gallagher, K.; Tyrberg, B.; Assadi-Porter, F.M.; et al. Artificial sweeteners stimulate adipogenesis and suppress lipolysis independently of sweet taste receptors. J. Biol. Chem. 2013, 288, 32475–32489. [Google Scholar] [CrossRef] [PubMed]
  104. Masubuchi, Y.; Nakagawa, Y.; Medina, J.; Nagasawa, M.; Kojima, I.; Rasenick, M.M.; Inagaki, T.; Shibata, H. T1R3 homomeric sweet taste receptor regulates adipogenesis through Galphas-mediated microtubules disassembly and Rho activation in 3T3-L1 cells. PLoS ONE 2017, 12, e0176841. [Google Scholar] [CrossRef]
  105. Simon, B.R.; Learman, B.S.; Parlee, S.D.; Scheller, E.L.; Mori, H.; Cawthorn, W.P.; Ning, X.; Krishnan, V.; Ma, Y.L.; Tyrberg, B.; et al. Sweet taste receptor deficient mice have decreased adiposity and increased bone mass. PLoS ONE 2014, 9, e86454. [Google Scholar] [CrossRef]
  106. Avau, B.; Bauters, D.; Steensels, S.; Vancleef, L.; Laermans, J.; Lesuisse, J.; Buyse, J.; Lijnen, H.R.; Tack, J.; Depoortere, I. The Gustatory Signaling Pathway and Bitter Taste Receptors Affect the Development of Obesity and Adipocyte Metabolism in Mice. PLoS ONE 2015, 10, e0145538. [Google Scholar] [CrossRef] [Green Version]
Table
Table 1. Overview of expression pattern and function of ectopic taste receptors.
Table 1. Overview of expression pattern and function of ectopic taste receptors.
OrganCell TypeReceptorFunctionReference
IntestineTuft cellTas1r3Regulation of epithelial homeostasis [61]
Tas2rsSensing the microbe-derived molecules and secretes IL-25[59]
EECsTas1r3Mediating cellular responses to artificial non-nutritive sweeteners[74]
Respiratory tractsTuft cellTas2rsRelease of acetylcholine to activate nociceptive neurons [46,62]
Tas1r3Alleviation of bitter tastants-evoked responses upon glucose stimulation[45]
Smooth muscleTas2rsInducing intracellular Ca2+ responses
Relaxation of airway smooth muscles and tracheal tension
Alleviation of the asthmatic symptoms of mouse models for allergic airway inflammation and bronchial hyperresponsiveness		[88,89,90,91,92]
Ciliated cellTAS2RsEliciting intracellular Ca2+ responses and accelerating ciliary beat frequency[94]
GingivaSCCsTas2rsAlleviation of periodontitis[39]
ThymusTuft cellTas2rsEstablishment of the microenvironment necessary for immune cells maturation[49]
Urinary tractTuft cellTas1r1,
Tas1r3,
Tas2rs		Monitoring the contents of the urethral lumen[51]
Umbrella cellTas1r2,
Tas1r3		Contract bladder smooth muscle [84]
Tas2rsRelaxation of smooth muscle contractions[85]
Pancreasβ-cellsTas1r2,
Tas1r3		Induction and potentiation of insulin secretion [77,78]
BrainNeuronsTas1r2Eliciting intracellular Ca2+ responses to artificial sweeteners[80]
Tanycytes,
perivascular cells		Tas1r2Eliciting intracellular Ca2+ responses to artificial sweeteners in tanycytes[81]
UnknownTas2rsUnknown[82,83]
HeartFibroblastTas1r1,
Tas1r3		Unknown[86]
CardiomyocyteTas2rsRegulation of cardiac and aortic pressure[86,87]
Vascular systemsSmooth muscleTas2rsRelaxation of vascular smooth muscles[93]
Immune cellsT cellsTas1rs
Tas2rs		Cell migration
Secretion of TNF-α		[95]
[100]
MacrophagesTas1rs
Tas2rs		Chemotaxis
Facilitation of phagocytosis		[95]
[102]
Adipose tissuePreadipocyteTas1r2,
Tas1r3		Differentiation of preadipocyte-like cells into mature adipocytes [104]
TAS2R38Unknown[106]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ki, S.Y.; Jeong, Y.T. Taste Receptors beyond Taste Buds. Int. J. Mol. Sci. 2022, 23, 9677. https://doi.org/10.3390/ijms23179677

AMA Style

Ki SY, Jeong YT. Taste Receptors beyond Taste Buds. International Journal of Molecular Sciences. 2022; 23(17):9677. https://doi.org/10.3390/ijms23179677

Chicago/Turabian Style

Ki, Su Young, and Yong Taek Jeong. 2022. "Taste Receptors beyond Taste Buds" International Journal of Molecular Sciences 23, no. 17: 9677. https://doi.org/10.3390/ijms23179677

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop