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Volume 2 Issue 1
Feb.  2020
Article Contents


Receptor, signal transduction and evolution of sweet, umami and bitter taste

  • Corresponding author: Zhenhui Liu, zhenhuiliu@ouc.edu.cn
  • Received Date: 2019-06-11
    Accepted Date: 2019-08-28
    Published online: 2019-11-25
  • Edited by Jiamei Li.
  • Like olfaction, the sense of taste allows the detection and discrimination of chemicals in the environment. However, while olfaction is specialized in the detection of volatile chemicals, taste is restricted to the detection of contact-chemicals. Two families of mammalian taste receptors, T1R and T2R, involved in recognition of sweet, umami (the taste of monosodium glutamate) and bitter stimuli have been identified and characterized. Although much progress has been made in studies on the basic mechanisms of taste recognition and signal transduction in mammals, we are still far from a full understanding of different taste qualities. This review presents a current perspective on sweet, bitter and umami taste receptors and their signal transduction mechanism. We also discuss the evolution of taste and taste-related molecules.
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Receptor, signal transduction and evolution of sweet, umami and bitter taste

    Corresponding author: Zhenhui Liu, zhenhuiliu@ouc.edu.cn
  • 1. Department of Marine Biology, Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao 266003, China
  • 2. Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266003, China

Abstract: Like olfaction, the sense of taste allows the detection and discrimination of chemicals in the environment. However, while olfaction is specialized in the detection of volatile chemicals, taste is restricted to the detection of contact-chemicals. Two families of mammalian taste receptors, T1R and T2R, involved in recognition of sweet, umami (the taste of monosodium glutamate) and bitter stimuli have been identified and characterized. Although much progress has been made in studies on the basic mechanisms of taste recognition and signal transduction in mammals, we are still far from a full understanding of different taste qualities. This review presents a current perspective on sweet, bitter and umami taste receptors and their signal transduction mechanism. We also discuss the evolution of taste and taste-related molecules.


  • Taste enables an animal to evaluate the nutritious content and the overall pleasure of food and thus acts as the last step in food acceptance or rejection behavior. Consequently, taste has evolved as a vital survival mechanism for animals (Callaway 2012). Although a wider range of taste modalities have been proposed, five basic taste qualities are currently recognized and widely accepted: sweet, umami, bitter, sour and salty. Each taste modality is mediated by distinct receptors located at the apical pole of the taste receptor cells (TRCs) that are found in taste buds (Barlow 2015; Chandrashekar et al. 2006).

    Taste receptors for salty and sour stimuli are ion channels (Boughter and Gilbertson 1999; Chandrashekar et al. 2010; Huang et al. 2006; Lindemann 2001; Nelson et al. 2001, 2002). Sweet, bitter and umami receptors belong to the family of G protein-coupled receptors (GPCRs), which possess a seven alpha-helical transmembrane core flanked by an extracellular amino termini and an intracellular carboxy-terminal tail. Here, we review current perspectives on sweet, bitter and umami taste receptors and their signal transduction mechanisms. The evolution of taste is also discussed.

Taste buds and taste receptor cells
  • Taste buds, which are peripheral structures responsible for sensing taste compounds in food and drink, are distributed across different papillae of the tongue as well as on the palate epithelium and on the wall of the throat (Miller 1995). There are three kinds of papillae located in the mammalian tongue, i.e., fungiform, foliate and circumvallate (Montmayeur and Matsunami 2002). The taste bud is an onion-shaped epithelial structure with 60-100 elongate cells. They are classified into at least three morphological types (type Ⅰ, type Ⅱ and type Ⅲ) and as many as five or more functional categories (Feng et al. 2014; Liman et al. 2014). Type Ⅰ (or glial-like) cells are the most common and are considered to be supporting cells which are wrapped around other cell types and orchestrate re-uptake or degradation of neurotransmitters; type Ⅱ are TRCs for sweet, bitter and umami detection; type Ⅲ are TRCs that appear to be sour and possibly salty detectors, although the cell type mediating salty taste remains ambiguous (Barlow 2015; Barlow and Klein 2015; Chaudhari 2014; Ishimaru et al. 2005; Roper 2007).

    The logic of how the taste system encodes information on chemical identity, that is, quality coding, is the subject of active investigation resulting in competing models of taste coding (Ohla et al. 2019; Scott and Giza 2000; Smith and St John 1999; Smith et al. 2000). In the "labeled line" model, the taste cells are selectively tuned to a specific modality, and are innervated by individually tuned nerve fibers. According to this model, the different transmission lines are separate, distinct, and parallel. The sensory afferent neurons are all "specialists" for a given quality. In the "across-fiber pattern" or "combinatorial coding" model, a single taste cell would recognizes a variety of different tastes and respond to multiple taste modalities. This model allows more flexibility in the responses of primary afferent fibers. The molecular and functional studies in mice seem to support the "labeled line" model (Chandrashekar et al. 2006), but more taste receptor cells and genes mediating different taste should be identified to distinguish the two models.

Taste receptors
Do more types of taste receptors exist?
  • It has been known that T1R2/T1R3 recognizes all sugar substances, TIR1/T1R3 is the umami receptor, and T2Rs is the bitter receptor. Are there any more taste receptors to detect sweet/umami/bitter substances? For example, is there a T1R1/T1R2 heterodimer or homodimer? If so, what are their functions? Kim et al. (2003) have found that, either alone or in all possible combinations, members of the T1R family was present in both circumvallate and fungiform papillae, and that T1R1 and T2R were coexpressed, in mice. Liao and Schultz (2003) showed that all three T1Rs were present selectively in taste receptor cells in human fungiform papillae. The existence of multiple sweet receptors was supported by electrophysiological and cross-adaptation studies (Danilova and Hellekant 2003; Froloff et al. 1998; Ninomiya et al. 1993; Schiffman et al. 1981). Furthermore, Damak et al. (2003) suggested that mice lacking the T1R3 receptor could not taste artificial sweeteners but still had an affinity for sugars, especially glucose, and could also perceive umami (Damak et al. 2003; Trivedi 2012a). This indicates that there are two different sweet mechanisms. However, no other members of the T1Rs family have been found by extensive searches of the close-to-complete human genome (Liao and Schultz 2003). Potential taste receptors may have no obvious sequence homology with T1Rs or T2Rs.

    There may exist other bitter receptor candidates besides the T2R family. Some studies have shown that bitter compounds such as caffeine and theophylline interact directly with phosphodiesterase (PDE) in taste tissue (Rosenzweig et al. 1999). Thus, it is speculated that the bitterness mechanism of caffeine is produced by inhibiting PDE (Rosenzweig et al. 1999). In addition, G protein-dependent and -independent pathways for denatonium signal transduction both exist in mammalian taste cells (Sawano et al. 2005). Therefore, more receptors that do not belong to GPCRs may be found in G protein-independent pathways.

Tongue map and brain map
  • Does the tongue have a "map" that responds to the five basic tastes of sweet, bitter, umami, salty and sour? For example, does circumvallate on the back of the tongue respond only to bitter, while foliate on the sides of the tongue recognize only sour? Recent molecular and functional data have revealed that all five basic modalities are present in all the taste papillae of the tongue (Adler et al. 2000; Hoon et al. 1999; Huang et al. 2006; Nelson et al. 2001, 2002). So, contrary to the popular belief in the early 1900s, there is no specific taste "map" on the tongue. However, each taste bud on the tongue responds to only one taste (Callaway 2012; Chen et al. 2011).

    How does the brain transform detection into perception? One of the leading theories is that the gustatory cortex was 'broadly tuned' with each neuron responding particularly well to one taste but still responding to others. Chen et al. (2011), however, found that sweet, bitter, salty and umami each was represented in its own separate cortical field, revealing the existence of a gustotopic map in the brain. Nevertheless, there may be some sensory crossover, with some cells in the bitter hotspot, for example, also responding to other tastes (Trivedi 2012b).

Taste signal transduction
  • Neuroscientists who study taste are just beginning to understand how and why the interaction of a few molecules on the tongue can trigger taste behaviors. Cells devoted to the detection of sweet, umami, and bitter stimuli share common signal transduction components (Meyerhof 2005). Generally, the first step is the ligand's interaction with a specific GPCR on the membrane. The G protein-mediated signaling pathway is then activated, initiating two second-messenger signaling cascades: cyclic adenosine monophosphate (cAMP) and phosphoinositide signaling, which are two parallel streams of intracellular events. Finally, depolarization of taste cells occurs, which activates nerve fibers (Gilbertson and Boughter 2003). Thus, taste signals are conveyed to the brain stem where central taste processing begins, eliciting adaptive responses (for details see review of Gilbertson and Boughter 2003; review of Lee and Owyang 2017; review of Lindemann 2001; review of Roper 2007).

    Here, we focused on the early events of taste signal transduction including the ligands, receptors, G proteins, scaffold proteins and their interactions.

  • It is apparent that different species enjoy different food compounds, and preferences differ even within the same species, for example, in humans. This leads us to consider the specificities of taste ligands. There is some research on this, although not very systematic. For example, Nelson et al. (2002) have shown that human T1R2/T1R3 receptors can recognize aspartame, cyclamate and various sweet proteins, but mouse T1R2/T1R3 cannot.

    Ligands recognized as taste receptors have been largely determined by in vitro heterologous expression and in vivo experiments. Human T1R2/T1R3 are known to recognize diverse natural sugars, such as sucrose and glucose, as well as synthetic sweeteners, such as saccharin and acesulfame-K (Li et al. 2002a, b; Roper 2007). Human T1R1/T1R3 functions as a broadly turned L-amino-acid sensor responding to most of the 20 standard amino acids, but not to their D-enantiomers (Nelson et al. 2002). When the taste stimulus is L-glutamate or monosodium glutamate (MSG), inosine 5-monophosphate (IMP) or guanosine 5-ribonucleotide (GMP) can enhance the response, which is the hallmark of umami taste (Li et al. 2002a, b; Roper 2007). More than 30 T2R bitter taste receptors have been discovered in mammals (Adler et al. 2000; Matsunami et al. 2000). The agonists for various T2Rs have also been identified and all of which were established as bitter tastants. Several receptors have been found to sense numerous bitter substances (Bufe et al. 2002). This is in line with the finding that the number of human bitter compounds is much larger than the number of human T2R genes. However, it was also found that different T2Rs selectively recognize different bitter compounds. For example, the human hT2R4 and mouse mT2R8 (a probable hT2R4 orthologue) is activated by denatonium (Chandrashekar et al. 2000); mouse mT2R5 (Chandrashekar et al. 2000) and rat rT2R9s (mT2R5 homologues; Bufe et al. 2002) respond to cycloheximide; human receptors T2R10 and T2R16 respond to strychnine and salicin, respectively (Bufe et al. 2002). Moreover, Mueller et al. (2005) demonstrated that mice lacking the receptor of mT2R5 lose the ability to recognize cycloheximide but can still detect other bitter compounds.

The binding of ligands and receptors
  • Given that T1R or T2R respond to a large wide range of taste compounds, one concept emerging is that there are multiple binding pockets with different selectivities for different ligands on the receptors (Roper 2007). Nevertheless, the question remains how the thousands of structurally diverse taste substances can be recognized by different combination pockets. It is more likely that receptors are broadly tuned or that other mechanisms exist.

    The large extracellular domain of T1Rs is the candidate site of critical binding pockets for the detection and discrimination of ligands. Walters (2002) analyzed the large extracellular domain of the sweet receptor T1R3 using a homology-modeled method based on the crystal structure of the metabotropic glutamate receptor (mGluR1). It showed that the regions corresponding to mGluR1 ligand-binding site in the model would respond to polyhydroxy compounds such as monosaccharides and disaccharides. Furthermore, using computer modeling, Temussi (2006) demonstrated that the large extracellular domain of T1R dimer forms a hinged ligand-binding pocket (also known as Venus flytrap, VFT). Experimental studies have confirmed that the large extracellular domains of T1R2 and T1R3 bind sugars, sweet amino acids and other sweet compounds (Morini et al. 2005). In addition, when the large extracellular N-terminal domain of T1Rs is expressed as soluble protein, the ligand-binding function remains (Nie et al. 2006).

    Further binding sites have been identified using chimeric constructs or site-directed mutations. By heterologous expression of the chimeras of mouse and human T1R1 and T1R3, Jiang et al. (2004) showed that a small area in the cysteine-rich region near the base of the N-terminus of T1R3 was required for receptor activity toward brazzein. Xu et al. (2004) demonstrated that the N-terminal VFT domain of T1R2 was required for the recognition of sweeteners such as aspartame and neotame, while the C-terminal transmembrane domain of T1R3 was required for the recognition of sweetener cyclamate and sweet inhibitor lactisole. Jiang et al. (2005) further proposed that the transmembrane domain of human T1R3 was likely to play a critical role in the interconversion of the sweet receptor from the ground state to the active state. They also identified several residues within the transmembrane domain of human T1R3 that account in large part for the species-specific response to cyclamate. Figure 1 shows the multiple binding sites between the GPCRs and ligands.

    Figure 1.  Schematic drawing of the multiple binding sites between sweet and umami taste receptors and ligands (based on the data of Xu et al. 2004; Roper 2007). The N-terminal extracellular domain of T1R2 is required for the binding of aspartame, neotame, saccharin and sucrose. The transmembrane domains of T1R3 are required for the binding of cyclamate, lactisole, saccharin and artificial sweeteners. The N-termini of T1R3 near the first transmembrane region is required for certain sweet-tasting proteins such as brazzein. L-Glutamate and IMP bind to the T1R1 subunit, respectively. In addition, the transmembrane domain of T1R1 or TIR2 is responsible for coupling to G proteins

    Unlike T1Rs, bitter receptor T2Rs has a shorter extracellular N-terminal, so its role in ligand recognition may not be as important as that of T1Rs. By domain swapping between hT2R43, hT2R44 and hT2R47, it was suggested that the extracellular loop 1 (EC1) of T2R43 was critical for its binding with IMNB (N-isopropyl-2-methyl-5-nitrobenzenesulfonamide) and 6-nitrosaccharin (Pronin et al. 2004). In addition, the extracellular loop 2 (EC2) was involved in binding to 6-nitrosaccharin, while the third extracellular loop (EC3) was not (Pronin et al. 2004). The structure-function relationships of bitter receptors hTAS2R46, -R43, and -R31 with their agonists were also revealed by calcium imaging of chimeric and mutant receptors (Brockhoff et al. 2007, 2010). It was found that the carboxyl-terminal regions, extracellular loops and transmembrane domains were all crucial for agonist selectivity (Brockhoff et al. 2007, 2010).

G proteins
  • Heterotrimeric guanine-nucleotide-binding proteins (G proteins), consisting of Gα and Gβγ subunits, function as signal transducers of the seven transmembrane helix of GPCRs. The specific interaction between GPCRs and heterotrimeric G proteins is important for maintaining the specificity and fidelity of signal relay (Gudermann et al. 1996; Neves et al. 2002). However, the native taste signaling pathways involving G protein are only poor understood. McLaughlin et al. (1992) identified a novel G protein α-subunit, α-gustducin, from taste tissue. The expression of α-gustducin messenger RNA was found in taste buds of all taste papillae including circumvallate, foliate and fungiform, but not in non-sensory portions of the tongue or other tissues, indicating a role of α-gustducin in taste transduction (McLaughlin et al. 1992). The role of α-gustducin in sweet, bitter and umami transduction was subsequently verified by comparing the behavioral and electrophysiological responses in α-gustducin knockout and wild-type mice (Caicedo et al. 2003; Danilova et al. 2006; He et al. 2004; Ruiz et al. 2003; Wong et al. 1996), or by transgenic expression of α-gustducin in α-gustducin-null mice (He et al. 2002). It has been demonstrated that other G protein subunits, i.e., Gβ3 and Gγ13, are coexpressed with α -gustducin in taste receptor cells, indicating the possible role of Gβ3 and Gγ13 in taste signal transduction (Huang et al. 1999, 2003; Max et al. 2001).

    How do the receptors interact with G proteins? Xu et al. (2004) demonstrated that T1R2, rather than T1R3, was critical for Gα15 coupling, requiring the transmembrane domain of T1R2 (Fig. 1). For T2Rs, the cytoplasmic loops and adjacent transmembrane segments have the greatest conservation, which is the predicted site for G protein binding. Thirty-seven C-terminal amino acids of gustducin and Gαi2 are indispensable for the T2R activity (Ueda et al. 2003). In addition, there are species differences in the map of receptor and G protein interactions. The G protein-coupling efficiency differs even between humans and rats (Xu et al. 2004).

The role of scaffold proteins
  • The role of scaffold proteins in taste signal transduction is poorly understood. Meyer et al. (2002) found that scaffold proteins such as ZO-1, ZO-2 and ZO-3 could interact with signaling protein Gα12, indicating a possible role in signal transduction. ZO-1/ZO-2 has also been shown to interact with tight junction protein claudins. Claudins were found to be present specifically in mouse taste papillae and human fungiform papillae (Michlig et al. 2007). Furthermore, ZO-1 can interact with Gγ13, a G protein gamma 13 subunit that plays a key role in taste signal transduction. ZO-1 and Gγ13 are co-located in taste bud cells (Liu et al. 2012). Therefore, scaffold proteins may be involved in taste signal transduction (Fig. 2), although precise mechanism by which this occurs is not yet clear.

    Figure 2.  The role of scaffold protein ZO-1/ZO-2 complex in taste signal transduction. ZO-1 interacts with Gγ13 and Gα12 through PDZ domain 1 and SH3 domain, respectively; it associates with claudins, ZO-2 and JAM (junctional adhesion molecules) through PDZ domains 1, 2, and 3, respectively (Ebnet et al. 2004; Fanning et al. 1998; Itoh et al. 2001); it associates with occludin through the GUK domain (Fanning et al. 1998) and with F-actin through an actin-binding region in the C-terminal half of the molecule (Fanning et al. 2002). The binding interactions among other tight junction proteins are not shown, and whether all of the interactions occur simultaneously remain to be determined

Taste evolution
  • Taste perception varies enormously across different species of animals. In birds, chickens did not seem to respond to sweet, while other nectar feeders showed strong preferences for sweet substances (Ganchrow et al. 1990; Shi and Zhang 2006); In mammals, different trophic groups differ in their selectivity and sensitivity to bitter or sweet compounds (Glendinning 1994; Xu et al. 2004). For example, a cat cannot taste sweet substances. Even between rats and mice, there were differences in electrophysiological properties, expression of markers and innervation in taste buds (Richter et al. 2004; Zaidi and Whitehead 2006). Ma et al. (2007) further suggested that there was a significant difference in the percentage of taste cells expressing signaling molecules between rats and mice. In fact, to adapt to different environments, taste organs have evolved to accommodate a distinct function in different species or lineages (Scott et al. 2001). For example, in vertebrates, taste is largely restricted to the tongue and palate, while in insects, gustatory neurons are more broadly distributed along the body, not only in the proboscis and pharynx, but also in the wings, legs, and female genitalia (Scott et al. 2001).

    Taste perception is mediated by taste receptor cells, in which taste receptors trigger the first step of taste signal transduction. Taste receptors specify attraction or aversion to food, so changes in these receptors may be directly related to adaptive changes in diet (Liman 2006). Taste receptors have now been identified in a large number of species including humans, other primates, mice, rats, fish and flies (Conte et al. 2003; Fischer et al. 2005; Go et al. 2005; Scott et al. 2001; Shi et al. 2003; Wang et al. 2004), enabling us to gain a better understanding of their evolutionary history and their associated functions.

    Shi and Zhang (2006) performed comparative evolutionary analyses of T1R and T2R genes from nine vertebrates. Three T1R genes were found in humans, mice, rats, dogs and opossums, but the number of T1R genes varies in some non-mammalian vertebrates. For example, fugu and pufferfish have five and six T1R genes, respectively (Shi and Zhang 2006). No T1R2 genes were found in chickens, which may account for their lack of sweet taste (Ganchrow et al. 1990; Shi and Zhang 2006). Amphibians (for example, western clawed frog) may have lost all T1R genes, but this requires confirmation (Shi and Zhang 2006). Cats have a mutation that disables one of the two genes that build a working sweet receptor, so cats cannot taste sweet substances. It is likely that the sweet-receptor gene became inactive in their evolutionary ancestor (Callaway 2012; Li et al. 2005). Jiang et al. (2012) showed that among 12 non-feline species in the order Carnivora, six species also had unique mutations in the sweet taste receptor gene (Jiang et al. 2012), suggesting that the ability to taste sweetness had been lost repeatedly over the course of evolution. In addition, dolphins lack the ability to build working umami and bitter taste receptors and pandas, a largely vegetarian member of Carnivora, lack umami receptors (Callaway 2012). There are four to six T2R genes in fish and three in chickens, but 21-42 in mammals and 49 in frogs (Shi and Zhang 2006), indicating a species- or lineage-specific gene duplication event. In mammals, the evolutionary relationships of T2R gene families have been described in detail (Conte et al. 2003; Fischer et al. 2005; Go et al. 2005; Lei et al. 2015; Sandau et al. 2015; Wang et al. 2004). Five T2R protein groups existed prior to the divergence of the primate and rodent lineages (Conte et al. 2003; Shi et al. 2003), and the species- or lineage-specific gene duplication and pseudogenization were shown to play an important role in altering of the T2R gene repertoire in individual primate species (Go et al. 2005; Zhao et al. 2010). When analyzing the rate of non-synonymous substitution versus synonymous substitution, positive selection of T1R and T2R genes was detected in vertebrates (Fischer et al. 2005; Shi and Zhang 2006; Shi et al. 2003; Wang et al. 2004). These two gene families, however, exhibited drastically different modes of evolution, with the former being conserved and latter being radical in the changes of gene number and gene sequences (Shi and Zhang 2006). Thus, functional divergence and specialization of taste receptors in vertebrates generally occur via adaptive evolution (Shi and Zhang 2006).

    It has long been known that mice and humans perceive various sweet substances through a single T1R2/T1R3 heterodimer (Li et al. 2002a, b; Zhao et al. 2003). Fish, however, appear to have different taste reception rules (Hashiguchi et al. 2007; Oike et al. 2007). Several T1R2 genes have been characterized in fish, all of which act as receptors to amino acids but not to sugars (Hashiguchi et al. 2007; Oike et al. 2007). Moreover, the T1R2 sequence similarity between fish and mammalian species is not high (Go 2006; Ishimaru et al. 2005; Pfister and Rodrigue 2005; Shi and Zhang 2006). This indicates that T1R2 is a changeable gene and several T1R2 genes may have existed before the separation of teleost fish and tetrapods (Oike et al. 2007). In the process of fish evolution, T1R2 gene replication events may have occurred giving T1Rs fish-specific functions such as a high sensitivity to amino acids. By contrast, mammalian T1R2/T1R3 receptors may have acquired sugar-responding ability (Hashiguchi et al. 2007; Oike et al. 2007).

    To date, T1R has been found only in fish, amphibians, birds and mammals, but not in invertebrates (Oike et al. 2007). No genes coding for bitter, sweet and umami taste receptors were found in the amphioxus Branchiostoma floridae (subphylum Cephalochordata) or the tunicate Ciona intestinalis (subphylum Urochordata), although olfactory receptors were identified in the former (Churcher and Taylor, 2009; Nordström et al. 2008). Interestingly, a large and diverse family of 68 candidate gustatory receptor (GR) genes was found in Drosophila (Clyne et al. 2000; Dunipace et al. 2001; Robertson et al. 2003; Scott et al. 2001). The carboxyl terminus of all GRs contains a signature motif which is also present in some members of the Drosophila odorant receptor (DOR) family, suggesting that they may share a common evolutionary origin. Scott et al. (2001) speculated that the GR gene family was likely to encode both olfactory and gustatory receptors in Drosophila, but not in vertebrates. Toshima and Tanimura (2012) proposed the presence of amino acid receptors and a monitoring system that regulates the feeding responses to amino acids in D. melanogaster. In addition, by comparing the molecular evolution of the GR genes along D. sechellia and D. simulans lineages, a rapid evolution of taste receptor genes during host specialization in D. sechellia was found. Furthermore, D. sechellia is losing GR genes nearly ten times faster than its generalist sibling D. simulans (McBride 2007). It is therefore likely that GR genes are subject to novel evolutionary pressures when insects enter new niches during host shifts or host specialization events (McBride 2007).

Future directions
  • In recent years, with the discovery of T1R and T2R receptors, much progress has been achieved in the research of sweet, umami and bitter taste. However, many fundamental issues remain to be resolved. For example, exactly how many taste receptors exist for different taste qualities? How do receptors recognize their specific ligands in taste bud cells and what are the pathways of taste signal transduction? How have taste receptors evolved? The answers to these basic questions will help us understand how taste works.

  • This work was supported by the grants of National Natural Science Foundation of China (31572259) and the Fundamental Research Funds for the Central Universities of China (201822020; 201841013).

Author contributions
  • ZR wrote the manuscript; ZL provided the outline for this manuscript and improved the text.

Compliance with ethical standards

    Conflict of interest

  • The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

  • Animal and human rights statement

  • This paper followed the ethical guidelines for animal and human rights established by Ocean University of China (Permit Number, SD2007695).

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