InteractiveFly: GeneBrief

Otopetrin-like a: Biological Overview | References

Gene name - Otopetrin-like a

Synonyms -

Cytological map position - 5A8-5A9

Function - transmembrane channel

Keywords - functions in distinct subsets of gustatory receptor neurons for repulsion and attraction to high and low levels of protons, respectively - expressed in the proboscis

Symbol - OtopLa

FlyBase ID: FBgn0259994

Genetic map position - chrX:5,626,277-5,648,506

Classification - pfam03189: Otopetrin

Cellular location - surface transmembrane

NCBI links: EntrezGene, Nucleotide, Protein

GENE orthologs: Biolitmine

Acid taste, evoked mainly by protons (H(+)), is a core taste modality for many organisms. The hedonic valence of acid taste is bidirectional: animals prefer slightly but avoid highly acidic foods. However, how animals discriminate low from high acidity remains poorly understood. To explore the taste perception of acid, the fruit fly was used as a model organism. Flies employ two competing taste sensory pathways to detect low and high acidity, and the relative degree of activation of each determines either attractive or aversive responses. Moreover, one member of the fly Otopetrin family, Otopetrin-like a (OtopLa), was established as a proton channel dedicated to the gustatory detection of acid. OtopLa defines a unique subset of gustatory receptor neurons and is selectively required for attractive rather than aversive taste responses. Loss of otopla causes flies to reject normally attractive low-acid foods. Therefore, the identification of OtopLa as a low-acid sensor firmly supports a competition model of acid taste sensation. Altogether, this study has discovered a binary acid-sensing mechanism that may be evolutionarily conserved between insects and mammals (Mi, 2021).

Sour taste, like sweet, bitter, salty, and umami tastes, represents a fundamental taste modality across many species ranging from insects to mammals. Typically, humans like slightly acidic foods such as lemon juice, which potentially indicates the presence of nutrients. In contrast, humans dislike highly acidic foods, which can cause digestive tract tissue injuries. The bivalent taste response to acid is also documented in rodents. Similar to mammals, the fruit fly, Drosophila melanogaster, prefers low levels of acid, which stimulate feeding and reproduction, and avoids high acid concentrations. Therefore, although flies and humans appear drastically different, the hedonic valence of their acid-taste response is similar: it can be either attractive or aversive, depending on the acid concentration of food. It is proposed that the bidirectional characteristic of acid perception constitutes an evolutionary fitness that enables animals to choose nutritious and reject unhealthy food sources. How do animals make this seemingly challenging decision? It is hypothesized that a taste-coding mechanism underlies the opposing feeding behavior triggered by low and high levels of acids. However, the molecular and cellular nature of the acid-taste coding has remained unclear (Mi, 2021).

Several lines of research demonstrate that type III taste receptor cells (TRCs) are responsible for acid sensing in mice. Nevertheless, the type III TRC population may be heterogeneous and contain different cell subtypes. Due to the lack of molecular markers and genetic tools to manipulate different subsets of type III TRCs, the question of how type III TRCs differentially respond to different concentrations of acid appears to be difficult to address in mammals. Moreover, other than eliciting taste sensation, acid also activates trigeminal nerves in the oral cavity of mammals, leading to burning or pain sensation. This side effect further confounds the investigation of sour-taste coding and sour-taste-triggered behavior in mammals. In contrast, flies exhibit much more pronounced and distinct taste responses to varying concentrations of acid than do mammals. Therefore, the fly serves as an excellent animal model to elucidate the taste coding of acid. This study reports that the fly mainly uses two different subsets of gustatory receptor neurons (GRNs) to selectively sense low or high concentrations of acids. The taste transduction pathways orchestrated by low- and high-acid GRNs antagonize each other, and the net behavioral response to a particular concentration of acid is predominantly determined by the relative activities of low- vs. high-acid GRNs (Mi, 2021).

Animals take advantage of highly diversified taste receptors and TRCs to detect varying taste substances, including sugar, salt, acid, and bitter compounds. In mammals, in contrast to the well-characterized sweet and bitter receptors, the molecular identity of sour-taste receptor had not been determined until a recent discovery showing that the Otopetrin (Otop) protein family functions as proton channels. In mice, one of the Otop family members, Otop1, is essential for sour-taste transduction. Despite this significant finding, the exact role played by Otop1 in discriminating low- from high-acid foods remained unclear. As the Otop family is fairly conserved between mammals and insects, it was of interest to see if the Otop family is also required for taste sensation of acids in Drosophila, given that no bona fide sour-taste receptors had been established in insects. One of the fly Otop orthologues, Otopetrin-like a (OtopLa), was shown to act as a proton channel and is selectively required for attractive taste sensation of acids in Drosophila. The fly OtopLa protein is localized at the tip of the GRN dendrite, the forefront site of taste sensory cells that is responsible for directly sensing tastant stimuli. Further, OtopLa defines a novel class of GRNs, which are largely distinct from other groups of GRNs responding to sugar, salt, or bitter tastants. Furthermore, genetic analysis showed that loss of otopetrin-like a (otopla) selectively abolishes the attractive acid-taste pathway, leaving the aversive pathway intact. Notably, the otopla mutant flies became abnormally averse to low concentrations of acid. Thus, this study provides strong genetic evidence to establish not only that the attractive and aversive taste pathways responsible for acid sensation exist but also that they are genetically segregated. Finally, by establishing OtopLa as a bona fide taste receptor for acid in flies, this work overturns the long-standing view that insects and mammals use fundamentally different gustatory receptors (Mi, 2021).

According to behavioral assays, the wild-type fly displays opposing taste responses to low and high concentrations of acid: low concentrations are attractive, whereas high concentrations are aversive. Thus, the hedonic valence of acid taste is closely associated with the concentration of acid that the animals detect. The bidirectional valence of sour taste is reminiscent of salty taste, which is also dependent on salt concentrations. Given these findings, a key question arises as to how the animals discern low- from high-acid foods. Rlectrophysiology analyses of different groups of taste sensilla provide an important clue to this question. Flies were found to mainly use L- and S-type sensilla to perceive low and high concentrations of acid, respectively. The L-type sensilla mediate an attractive pathway, whereas the S-type sensilla operate an aversive pathway for the response to acids. It is postulated that acid-taste signals relayed by low- and high-acid GRNs antagonize each other in the brain, where feeding decisions are made. When the fly encounters low-acid foods, the attractive pathway mediated by low-acid GRNs dominates the aversive pathway mediated by the high-acid GRNs, driving the animal to choose the low-acid food. Conversely, when the animal encounters high-acid foods, the aversive pathway dominates the attractive pathway, leading to the avoidance of high-acid foods (Mi, 2021).

In support of this hypothesis, genetic analysis reveals that otopla is specifically required for the attractive rather than aversive acid-taste response. Further, it was found that otopla is mostly expressed in the GRNs housed within the L-type rather than the S-type sensilla. In addition, recent work shows that a member of the ionotropic receptor (IR) family, Ir7a, is selectively required for the repulsive response to high concentrations of acetic acid in Drosophila. However, flies lacking Ir7a show normal attractive feeding responses to low concentrations of acetic acid. That study, combined with the present study on otopla, provides substantial evidence to support the model that the attractive and aversive pathways for acid sensation are segregated in the peripheral taste organ (Mi, 2021).

These findings lay the foundation for a more detailed analysis of the genetic program and neural circuit involved in sour-taste perception. In mammals, type III TRCs are mainly responsible for sour-taste sensation. Nevertheless, whether distinct subgroups of type III TRCs in the taste bud selectively respond to low or high acid remains an open question. Given the conservation of acid-taste sensation between flies and mammals, the acid-taste coding mechanism identified in the fly will inform the investigation of sour-taste coding in mammals, including humans (Mi, 2021).

Using multiple lines of evidence, these studies lead to the identification of OtopLa as a long-sought taste receptor for acid in Drosophila. First, genetic analyses show that OtopLa is both necessary and sufficient to orchestrate the attractive response to foods containing low concentrations of acid. In addition, loss of otopla has no effect on sweet, bitter, or salty tastes. Second, cell biological studies reveal that OtopLa is expressed in a group of GRNs different from sweet, bitter, and salty GRNs. Moreover, OtopLa proteins selectively reside in the distal portion of the dendrite, the forefront of the GRN responsible for detecting taste substances presented from the food environment. Last but not least, patch-clamp recordings reveal that OtopLa functions as a proton channel and can be directly activated by protons. Collectively, this work establishes OtopLa as a bona fide receptor that is dedicated to the attractive taste sensation of acids in Drosophila. Recent studies in mice show that the Otop1 proton channel is both necessary and sufficient for sour-taste transduction. In light of these discoveries in flies and mice, it is concluded that the Otop family is an evolutionarily conserved proton channel dedicated to taste the sensation of acids in both insects and mammals. Over the past two decades, various types of taste receptors, including sweet, bitter, and salty taste receptors, have been identified and functionally characterized in both invertebrates and vertebrates. Although insects and mammals exhibit a striking homology in taste responses, the molecular identities of their sweet, bitter, and salty taste receptors appear to be distantly related to each other. Consequently, there is a long-held view in the chemoreception field that taste receptors for insects and mammals are evolutionarily distant from each other. In this study, the discovery in the fly acid-taste sensation has overturned this notion. The Otop family represents the first class of taste receptors that is functionally conserved between insects and mammals. From an evolutionary perspective, it is proposed that Otop is a well-conserved proton channel family involved in acid-taste sensation throughout the animal kingdom. Thus, further research is needed to explore the gustatory role of the Otop family in other animal species, including humans (Mi, 2021).

otopla is necessary for the attractive taste sensation of both the strong acid HCl and the weak acids citric acid and malic acid. Psychophysical studies in human subjects report that weak acid usually tastes more sour than strong acid at the same pH40, implying that, in addition to protons, the undissociated weak acid molecules may also elicit sourness. These studies demonstrate that the proton channel OtopLa is broadly required for the taste sensation of both strong and weak acids. Therefore, it is proposed that the taste response to acids orchestrated by OtopLa mainly results from the gustatory stimuli of protons that are dissociated from either strong or weak acids. In addition, several members of the fly IR family are involved in taste responses to carbonation and acetic acid. As there has been no evidence showing that the IRs form a proton channel, the IRs are likely to be narrowly tuned to the specific structures of weak acids rather than to protons. Collectively, the fly may use different taste transduction pathways to perceive various acid molecules present in the environment (Mi, 2021).

In conclusion, given the significant conservation of taste receptors for acid between flies and mammals, the fly model will significantly advance understanding of the acid-taste sensation in other animals, including humans (Mi, 2021).

Requirement for an Otopetrin-like protein for acid taste in Drosophila

Receptors for bitter, sugar, and other tastes have been identified in the fruit fly Drosophila melanogaster, while a broadly tuned receptor for the taste of acid has been elusive. Previous work showed that such a receptor was unlikely to be encoded by a gene within one of the two major families of taste receptors in Drosophila, the ‘gustatory receptors' and ‘ionotropic receptors.' To identify the acid taste receptor, this study tested the contributions of genes encoding proteins distantly related to the mammalian Otopertrin1 (OTOP1) proton channel that functions as a sour receptor in mice. RNA interference (RNAi) knockdown or mutation by CRISPR/Cas9 of one of the genes, Otopetrin-Like A (OtopLA), but not of the others (OtopLB or OtopLC) severely impaired the behavioral rejection to a sweet solution laced with high levels of HCl or carboxylic acids and greatly reduced acid-induced action potentials measured from taste hairs. An isoform of OtopLA that was isolated from the proboscis was sufficient to restore behavioral sensitivity and acid-induced action potential firing in OtopLA mutant flies. At lower concentrations, HCl was attractive to the flies, and this attraction was abolished in the OtopLA mutant. Cell type-specific rescue experiments showed that OtopLA functions in distinct subsets of gustatory receptor neurons for repulsion and attraction to high and low levels of protons, respectively. This work highlights a functional conservation of a sensory receptor in flies and mammals and shows that the same receptor can function in both appetitive and repulsive behaviors (Ganguly, 2021).

The functional conservation of the Otop channels for acid taste in flies is striking given that chemosensory receptors tend to vary greatly in flies and mammals, which diverged ∼800 million y ago. In contrast to the Otop channels, the two major families of fly receptors (GRs and IRs), which function in tasting sugars, bitter compounds, acetic acid, amino acids, polyamines, N, N-diethyl-meta-toluamide (DEET), CO2, and other tastants are not present in mammals. The retention of Otop channels for acid taste in flies and mice is remarkable since the gross anatomies of the gustatory systems are very different. In addition, the taste receptor cells in flies are neurons, while they are modified epithelial cells in mammals (Ganguly, 2021).

The conserved role for Otop proteins for acid taste in flies and mammals cannot be explained by greater selective pressure for maintaining a receptor for a mineral (e.g., H+) versus organic molecules since other minerals (Ca2+ and Na+) are sensed in flies through IRs, which are not present in mammals. Thus, the retention of Otop channels for acid taste in flies and mammals underscores the very strong selection for this acid sensor for animal survival. Otop-related proteins are encoded in many distantly related terrestrial and aquatic vertebrates ranging from the platypus to frogs and pufferfish, as well as ancient invertebrates such as worms and insect disease vectors, including Aedes aegypti. Thus, despite the considerable diversity of most chemosensory receptors, it is plausible that Otop channels endow a large proportion of the animal kingdom with acid taste (Ganguly, 2021).

A question concerns the cellular mechanism through which the sensation of protons is detected. OtopLA is expressed in the four classes of GRNs in taste hairs (A to D). The B and D GRNs respond to aversive tastants (B, bitter, high Na+ etc; D, Ca2+, high Na+, K+), while the A and C GRNs are activated by chemicals that stimulate consumption (A, sugars, low Na+ fatty acids, etc; C, water). The data indicate that both B and D GRNs contribute to acid repulsion but that B GRNs comprise the major class required for acid repulsion, while D GRNs are the minor class. In support of this conclusion, RNAi knockdown of B but not D GRNs impaired acid repulsion. In addition, the OtopLA1 mutant phenotype was fully rescued by expression of the OtopLAp transgene in B GRNs but only partially rescued the deficit by expression of OtopLAp in D GRNs. In addition, the data indicate that both A and C GRNs contribute to the modest attraction to 0.01 HCl in wild-type flies. This attraction is eliminated in the OtopLA1 mutant. The C GRNs may be more important, as expression of the OtopLAp transgene in A GRNs reduced the impairment in the mutant, but the suppression of the phenotype fell below the threshold for statistical significance (Ganguly, 2021).

It has been reported that acids cause repulsion of sugary foods by direct activation of B GRNs and suppression of sugar-induced activation of A GRNs. This previous study focused on behavioral responses to carboxylic acids, and this study repeated this finding for citric acid. However, at the cellular level, when the pH of sucrose was decreased, no reduced sucrose-induced action potentials were induced. Thus, it is concluded that protons do not suppress A GRNs. Rather, it is suggest that A GRNs are inhibited by certain organic anion moieties of carboxylic acids. A mechanism by which the activities of both A GRNs and B GRNs are affected by carboxylic acids, but only B GRNs by protons could provide a coding mechanism for differentiating between protons and carboxylic acids (Ganguly, 2021).

Following submission of the initial version of this manuscript, another group also reported a role for OtopLA in acid taste in Drosophila (Mi, 2021). These researchers found that OtopLA is required for attractive responses to low concentrations of acids, as did this study, but not for aversive responses to higher concentrations of acids. However, even in wild-type controls, they did not observe significant repulsion until the pH was reduced to high levels (≤2) that may be damaging to cells. At these very low pHs, the nociceptive response is likely to have a major contribution to avoidance. Mi (2021). also reported that the flies exhibited a much higher level of attraction to acids than what was observed in the current study. The differences in levels of attraction and repulsion might be due to variations in fly food between laboratories, the precise ages of the flies, hours of starvation, or a combination of these factors. Nevertheless, although the level of acid attraction differs, both studies find that the deficit in attraction in OtopLA mutants can be suppressed by expression of a wild-type transgene in A GRNs. In addition, this study found that this phenotype is suppressed by expression of the OtopLA rescue transgene in C GRN (Ganguly, 2021).

Another difference between the current report and that of Mi (2021) is that they reported that expression of OtopLAa in human embryonic kidney 293 (HEK293) cells led to the appearance of inward currents in response to acid stimuli (pH range 6 to 3). It has been previously demonstrated that both vertebrate and invertebrate Otop proteins form proton channels. However, this study did not observe any acid-induced currents using stimuli as low as pH 3.0 for either OtopLAp or OtopLAa (FBgn0259994) expressed in either HEK293 cells or Xenopus oocytes, even though surface expression was detected when the channels were tagged with GFP. There are several possible reasons why the Drosophila OtopLA channel did not generate functional currents in either cell type. One possibility is that the native system provides factors or binding partners necessary to gate the channels. It is noted that OtopLA is the only one of the Drosophila Otop channels to have a large extracellular domain between transmembrane domains 5 and 6, which might bind ligands or proteins (Ganguly, 2021).

Together, these data point to a complex role of the OtopLA channel in the gustatory system of Drosophila, where it is expressed in multiple types of sensory cells and can mediate both attractive and aversive responses. Interestingly, humans also find acids appetitive at low concentrations and aversive at higher concentrations. The elucidation of the cellular and molecular mechanism of acid-sensing that is described in this study can serve as the basis for further understanding as to how animals assign valence to stimuli that vary only in intensity (Ganguly, 2021).

Functions of Otopetrin orthologs in other species

The roles of two extracellular loops in proton sensing and permeation in human Otop1 proton channel

Otopetrin (Otop) proteins were recently found to function as proton channels, with Otop1 revealed to be the sour taste receptor in mammals. Otop proteins contain twelve transmembrane segments (S1-S12) which are divided into structurally similar N and C domains. The mechanisms by which Otop channels sense extracellular protons to initiate gating and conduct protons once the channels are activated remains largely elusive. This study shows that two extracellular loops are playing key roles in human Otop1 channel function. Residue H229 in the S5-S6 loop is critical for proton sensing of Otop1. Further, the data reveal that the S11-12 loop is structurally and functionally essential for the Otop1 channel and that residue D570 in this loop regulates proton permeation into the pore formed by the C domain. This study sheds light on the molecular mechanism behind the structure and function of this newly identified ion channel family (Li, 2022).

Structural motifs for subtype-specific pH-sensitive gating of vertebrate otopetrin proton channels

Otopetrin (OTOP) channels are proton-selective ion channels conserved among vertebrates and invertebrates, with no structural similarity to other ion channels. There are three vertebrate OTOP channels (OTOP1, OTOP2, and OTOP3), of which one (OTOP1) functions as a sour taste receptor. Whether extracellular protons gate OTOP channels, in addition to permeating them, was not known. This study compared the functional properties of the three murine OTOP channels using patch-clamp recording and cytosolic pH microfluorimetry. OTOP1 and OTOP3 are both steeply activated by extracellular protons, with thresholds of pHo <6.0 and 5.5, respectively, and kinetics that are pH-dependent. In contrast, OTOP2 channels are broadly active over a large pH range (pH 5 - pH 10) and carry outward currents in response to extracellular alkalinization (>pH 9.0). Strikingly, it was possible to change the pH-sensitive gating of OTOP2 and OTOP3 channels by swapping extracellular linkers that connect transmembrane domains. Swaps of extracellular linkers in the N domain, comprising transmembrane domains 1-6, tended to change the relative conductance at alkaline pH of chimeric channels, while swaps within the C domain, containing transmembrane domains 7-12, tended to change the rates of OTOP3 current activation. It is conclude that members of the OTOP channel family are proton-gated (acid-sensitive) proton channels and that the gating apparatus is distributed across multiple extracellular regions within both the N and C domains of the channels. In addition to the taste system, OTOP channels are expressed in the vertebrate vestibular and digestive systems. The distinct gating properties described in this study may allow them to subserve varying cell-type specific functions in these and other biological systems (Teng, 2022).

Cellular and Neural Responses to Sour Stimuli Require the Proton Channel Otop1

The sense of taste allows animals to sample chemicals in the environment prior to ingestion. Of the five basic tastes, sour, the taste of acids, had remained among the most mysterious. Acids are detected by type III taste receptor cells (TRCs), located in taste buds across the tongue and palate epithelium. The first step in sour taste transduction is believed to be entry of protons into the cell cytosol, which leads to cytosolic acidification and the generation of action potentials. The proton-selective ion channel Otop1 is expressed in type III TRCs and is a candidate sour receptor. This study tested the contribution of Otop1 to taste cell and gustatory nerve responses to acids in mice in which Otop1 was genetically inactivated (Otop1-KO mice). It was first shown that Otop1 is required for the inward proton current in type III TRCs from different parts of the tongue that are otherwise molecularly heterogeneous. It was next shown that in type III TRCs from Otop1-KO mice, intracellular pH does not track with extracellular pH and that moderately acidic stimuli do not elicit trains of action potentials, as they do in type III TRCs from wild-type mice. Moreover, gustatory nerve responses in Otop1-KO mice were severely and selectively attenuated for acidic stimuli, including citric acid and HCl. These results establish that the Otop1 proton channel plays a critical role in acid detection in the mouse gustatory system, evidence that it is a bona fide sour taste receptor (Teng, 2019).

Sour Sensing from the Tongue to the Brain

The ability to sense sour provides an important sensory signal to prevent the ingestion of unripe, spoiled, or fermented foods. Taste and somatosensory receptors in the oral cavity trigger aversive behaviors in response to acid stimuli. This study shows that the ion channel Otopetrin-1, a proton-selective channel normally involved in the sensation of gravity in the vestibular system, is essential for sour sensing in the taste system. Knockout of Otop1 eliminates acid responses from sour-sensing taste receptor cells (TRCs). In addition, this study shows that mice engineered to express otopetrin-1 in sweet TRCs have sweet cells that also respond to sour stimuli. Next, the taste ganglion neurons mediating each of the five basic taste qualities were genetically identified, and sour taste was demonstrated to use its own dedicated labeled line from TRCs in the tongue to finely tuned taste neurons in the brain to trigger aversive behaviors (Zhang, 2019).

Structures of the otopetrin proton channels Otop1 and Otop3

Otopetrins (Otop1-Otop3) comprise one of two known eukaryotic proton-selective channel families. Otop1 is required for otoconia formation and a candidate mammalian sour taste receptor. This study reports cryo-EM structures of zebrafish Otop1 and chicken Otop3 in lipid nanodiscs. The structures reveal a dimeric architecture, with each subunit forming 12 transmembrane helices divided into structurally similar amino (N) and carboxy (C) domains. Cholesterol-like molecules occupy various sites in Otop1 and Otop3 and occlude a central tunnel. In molecular dynamics simulations, hydrophilic vestibules formed by the N and C domains and in the intrasubunit interface between N and C domains form conduits for water entry into the membrane core, suggesting three potential proton conduction pathways. By mutagenesis, the roles of charged residues in each putative permeation pathway were tested. The results provide a structural basis for understanding selective proton permeation and gating of this conserved family of proton channels (Saotome, 2019).


Search PubMed for articles about Drosophila

Ganguly, A., Chandel, A., Turner, H., Wang, S., Liman, E. R. and Montell, C. (2021). Requirement for an Otopetrin-like protein for acid taste in Drosophila. Proc Natl Acad Sci U S A 118(51). PubMed ID: 34911758

Li, B., Wang, Y., Castro, A., Ng, C., Wang, Z., Chaudhry, H., Agbaje, Z., Ulloa, G. A. and Yu, Y. (2022). The roles of two extracellular loops in proton sensing and permeation in human Otop1 proton channel. Commun Biol 5(1): 1110. PubMed ID: 36266567

Mi, T., Mack, J. O., Lee, C. M. and Zhang, Y. V. (2021). Molecular and cellular basis of acid taste sensation in Drosophila. Nat Commun 12(1): 3730. PubMed ID: 34140480

Saotome, K., Teng, B., Tsui, C. C. A., Lee, W. H., Tu, Y. H., Kaplan, J. P., Sansom, M. S. P., Liman, E. R. and Ward, A. B. (2019). Structures of the otopetrin proton channels Otop1 and Otop3. Nat Struct Mol Biol 26(6): 518-525. PubMed ID: 31160780

Teng, B., Wilson, C. E., Tu, Y. H., Joshi, N. R., Kinnamon, S. C. and Liman, E. R. (2019). Cellular and Neural Responses to Sour Stimuli Require the Proton Channel Otop1. Curr Biol 29(21): 3647-3656. PubMed ID: 31543453

Teng, B., Kaplan, J. P., Liang, Z., Krieger, Z., Tu, Y. H., Burendei, B., Ward, A. B. and Liman, E. R. (2022). Structural motifs for subtype-specific pH-sensitive gating of vertebrate otopetrin proton channels. Elife 11. PubMed ID: 35920807

Zhang, J., Jin, H., Zhang, W., Ding, C., O'Keeffe, S., Ye, M. and Zuker, C. S. (2019). Sour Sensing from the Tongue to the Brain. Cell 179(2): 392-402 e315. PubMed ID: 31543264

Biological Overview

date revised: 18 November 2022

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