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Key Points Taste buds are composed of two excitable cell types and a glia-like cell; each type of cell has distinct functions. Basic taste qualities are detected by G protein-coupled type 1 and type 2 taste receptors, by other receptors and ion channels, and possibly by transporters. ATP is an afferent taste transmitter and is secreted by taste bud cells through an unconventional, non-vesicular release mechanism. ATP, serotonin and GABA mediate cell–cell interactions in the taste bud that may shape transmission to sensory afferent fibres. Controversy remains regarding whether peripheral taste coding follows a labelled-line or combinatorial pattern. Taste preferences and appetites seem to have a genetic component that is being revealed by molecular and population studies. Mammals detect the nutrient content, palatability and potential toxicity of food through taste buds that are present mainly in the tongue. In this Review, Roper and Chaudhari discuss the taste bud cells, receptors and transmitters that are involved in taste detection, how these cells communicate with sensory afferent fibres, and peripheral taste coding. The past decade has witnessed a consolidation and refinement of the extraordinary progress made in taste research. This Review describes recent advances in our understanding of taste receptors, taste buds, and the connections between taste buds and sensory afferent fibres. The article discusses new findings regarding the cellular mechanisms for detecting tastes, new data on the transmitters involved in taste processing and new studies that address longstanding arguments about taste coding.

High concentrations of salt activate sour- and bitter-taste-sensing cells in the tongues of mice, and genetic silencing of these pathways abolishes behavioural aversion to concentrated salt; this ‘co-opting’ of the two primary aversive taste pathways (sour and bitter) may have evolved so that high salt levels reliably trigger behavioural rejection. The taste of too much salt In contrast to the other four basic tastes (sweet, umami, sour and bitter), which are either appetitive or aversive, sodium salt can be both attractive and repulsive, depending on concentration. Lower concentrations of salt are perceived by cells expressing the sodium channel ENaC. In this study, Charles Zuker and colleagues show that high levels of salt activate the sour and bitter taste-sensing cells, and that salt-avoidance behaviours are abolished in mice lacking these pathways. The authors conclude that 'co-opting' the two primary aversive taste pathways causes the animals to reject foodstuffs containing extreme — and potentially harmful — levels of salt. Given current concerns about excessive dietary salt intake in humans, this work raises the prospect of developing selective receptor-cell modulators to help to control or even satisfy our strong appetite for salt without the potential ill effects of too much sodium. In the tongue, distinct classes of taste receptor cells detect the five basic tastes; sweet, sour, bitter, sodium salt and umami 1 , 2 . Among these qualities, bitter and sour stimuli are innately aversive, whereas sweet and umami are appetitive and generally attractive to animals. By contrast, salty taste is unique in that increasing salt concentration fundamentally transforms an innately appetitive stimulus into a powerfully aversive one 3 , 4 , 5 , 6 , 7 . This appetitive–aversive balance helps to maintain appropriate salt consumption 3 , 4 , 6 , 8 , and represents an important part of fluid and electrolyte homeostasis. We have shown previously that the appetitive responses to NaCl are mediated by taste receptor cells expressing the epithelial sodium channel, ENaC 8 , but the cellular substrate for salt aversion was unknown. Here we examine the cellular and molecular basis for the rejection of high concentrations of salts. We show that high salt recruits the two primary aversive taste pathways by activating the sour- and bitter-taste-sensing cells. We also demonstrate that genetic silencing of these pathways abolishes behavioural aversion to concentrated salt, without impairing salt attraction. Notably, mice devoid of salt-aversion pathways show unimpeded, continuous attraction even to very high concentrations of NaCl. We propose that the ‘co-opting’ of sour and bitter neural pathways evolved as a means to ensure that high levels of salt reliably trigger robust behavioural rejection, thus preventing its potentially detrimental effects on health.

Taste-receptor cells use distinct semaphorins to guide wiring of the peripheral taste system; targeted ectopic expression of SEMA3A or SEMA7A leads to bitter neurons responding to sweet tastes or sweet neurons responding to bitter tastes. Bittersweet tinkering with the taste system Taste cells experience a very rapid turnover, having life spans of only 5 to 20 days, but it is not yet known how the constantly replenishing taste cells re-establish appropriate connections with their respective ganglion neurons. Here, Charles Zuker and colleagues reveal that taste receptor cells make connections with neurons representing the same taste quality based on the different axon guidance molecules expressed by each taste receptor cell type. To demonstrate this molecular logic, the authors forced a sweet taste receptor cell to establish a connection with a bitter taste quality neuron simply through the ectopic expression of the bitter guidance molecule in the sweet taste receptor cell. These findings provide insights into how the gustatory system remains organized and specific despite experiencing cell turnover on such a large scale. In mammals, taste buds typically contain 50–100 tightly packed taste-receptor cells (TRCs), representing all five basic qualities: sweet, sour, bitter, salty and umami 1 , 2 . Notably, mature taste cells have life spans of only 5–20 days and, consequently, are constantly replenished by differentiation of taste stem cells 3 . Given the importance of establishing and maintaining appropriate connectivity between TRCs and their partner ganglion neurons (that is, ensuring that a labelled line from sweet TRCs connects to sweet neurons, bitter TRCs to bitter neurons, sour to sour, and so on), we examined how new connections are specified to retain fidelity of signal transmission. Here we show that bitter and sweet TRCs provide instructive signals to bitter and sweet target neurons via different guidance molecules (SEMA3A and SEMA7A) 4 , 5 , 6 . We demonstrate that targeted expression of SEMA3A or SEMA7A in different classes of TRCs produces peripheral taste systems with miswired sweet or bitter cells. Indeed, we engineered mice with bitter neurons that now responded to sweet tastants, sweet neurons that responded to bitter or sweet neurons responding to sour stimuli. Together, these results uncover the basic logic of the wiring of the taste system at the periphery, and illustrate how a labelled-line sensory circuit preserves signalling integrity despite rapid and stochastic turnover of receptor cells.

The turnover and re-establishment of peripheral taste synapses is vital to maintain connectivity between primary taste receptor cells and the gustatory neurons which relay taste information from the tongue to the brain. Despite the importance of neuron-taste cell reconnection, the mechanisms governing synapse assembly in the taste bud are largely unknown. To determine whether nerve fiber connectivity is an initiating factor for the recruitment of presynaptic machinery in taste receptor cells, we use the expression of CALHM1 and Bassoon to identify presynaptic sites in type II (sweet, umami, bitter) and type III (sour) taste receptor cells, respectively. Under homeostatic conditions, the vast majority (>90%) of presynaptic sites are directly adjacent to nerve fibers (contacted). In the days immediately following gustatory nerve transection and denervation of taste buds, Bassoon and CALHM1 puncta are markedly reduced. This suggests that nerve fiber innervation is crucial for the recruitment and maintenance of presynaptic sites. During nerve fiber regeneration into the taste bud, presynaptic sites begin to replenish but are not as frequently contacted by nerve fibers as intact controls (35–54% compared to >90%). This reveals that taste cells rely on gustatory fiber innervation to organize presynaptic sites. Additionally, our finding that presynaptic sites are not as frequently contacted by regenerating axons suggests a model whereby trophic factors secreted by gustatory nerve fibers prompt taste receptor cells to produce and/or aggregate presynaptic specializations at the cell membrane prior to contact. This, in turn, may guide neurons to form mature synapses. These findings provide new insights into the mechanisms driving synaptogenesis and synaptic plasticity within the rapidly changing taste bud environment.

Much of what we learned in school about how we taste is wrong. Progress in understanding how taste works is providing insights that may help in the management of obesity, diabetes, and other illnesses.

Striking taste disturbances are reported in cancer patients treated with Hedgehog (HH)-pathway inhibitor drugs, including sonidegib (LDE225), which block the HH pathway effector Smoothened (SMO). We tested the potential for molecular, cellular, and functional recovery in mice from the severe disruption of taste-organ biology and taste sensation that follows HH/SMO signaling inhibition. Sonidegib treatment led to rapid loss of taste buds (TB) in both fungiform and circumvallate papillae, including disruption of TB progenitor-cell proliferation and differentiation. Effects were selective, sparing nontaste papillae. To confirm that taste-organ effects of sonidegib treatment result from HH/SMO signaling inhibition, we studied mice with conditional global or epithelium-specific Smo deletions and observed similar effects. During sonidegib treatment, chorda tympani nerve responses to lingual chemical stimulation were maintained at 10 d but were eliminated after 16 d, associated with nearly complete TB loss. Notably, responses to tactile or cold stimulus modalities were retained. Further, innervation, which was maintained in the papilla core throughout treatment, was not sufficient to sustain TB during HH/SMO inhibition. Importantly, treatment cessation led to rapid and complete restoration of taste responses within 14 d associated with morphologic recovery in about 55% of TB. However, although taste nerve responses were sustained, TB were not restored in all fungiform papillae even with prolonged recovery for several months. This study establishes a physiologic, selective requirement for HH/SMO signaling in taste homeostasis that includes potential for sensory restoration and can explain the temporal recovery after taste dysgeusia in patients treated with HH/SMO inhibitors.

Taste bud cells regenerate throughout life. Taste bud maintenance depends on continuous replacement of senescent taste cells with new ones generated by adult taste stem cells. More than a century ago it was shown that taste buds degenerate after their innervating nerves are transected and that they are not restored until after reinnervation by distant gustatory ganglion neurons. Thus, neuronal input, likely via neuron-supplied factors, is required for generation of differentiated taste cells and taste bud maintenance. However, the identity of such a neuron-supplied niche factor(s) remains unclear. Here, by mining a published RNA-sequencing dataset of geniculate ganglion neurons and by in situ hybridization, we demonstrate that R-spondin-2, the ligand of Lgr5 and its homologs Lgr4/6 and stem-cell-expressed E3 ligases Rnf43/Znrf3, is expressed in nodose-petrosal and geniculate ganglion neurons. Using the glossopharyngeal nerve transection model, we show that systemic delivery of R-spondin via adenovirus can promote generation of differentiated taste cells despite denervation. Thus, exogenous R-spondin can substitute for neuronal input for taste bud cell replenishment and taste bud maintenance. Using taste organoid cultures, we show that R-spondin is required for generation of differentiated taste cells and that, in the absence of R-spondin in culture medium, taste bud cells are not generated ex vivo. Thus, we propose that R-spondin-2 may be the long-sought neuronal factor that acts on taste stem cells for maintaining taste tissue homeostasis.

The variety of taste sensations, including sweet, umami, bitter, sour, and salty, arises from diverse taste cells, each of which expresses specific taste sensor molecules and associated components for downstream signal transduction cascades. Recent years have witnessed major advances in our understanding of the molecular mechanisms underlying transduction of basic tastes in taste buds, including the identification of the bona fide sour sensor H+ channel OTOP1, and elucidation of transduction of the amiloride-sensitive component of salty taste (the taste of sodium) and the TAS1R-independent component of sweet taste (the taste of sugar). Studies have also discovered an unconventional chemical synapse termed “channel synapse” which employs an action potential-activated CALHM1/3 ion channel instead of exocytosis of synaptic vesicles as the conduit for neurotransmitter release that links taste cells to afferent neurons. New images of the channel synapse and determinations of the structures of CALHM channels have provided structural and functional insights into this unique synapse. In this review, we discuss the current view of taste transduction and neurotransmission with emphasis on recent advances in the field.

The tamoxifen-inducible Cre-loxP system is an indispensable experimental tool in life sciences for inducing spatiotemporally controlled genetic recombination in the target tissues of living animals. The use of this technology is expected to increase in taste research. However, the direct effects of tamoxifen on taste buds remain largely unexplored. Here, we demonstrate that tamoxifen reduces cell supply to the taste buds in a dose-dependent manner. RNA sequencing of the circumvallate epithelium revealed that tamoxifen induced a transcriptional shift from proliferation to differentiation. The genes regulating the cell cycle were downregulated, whereas genes promoting the differentiation of epithelial cells and keratinocytes were upregulated. Within taste buds, Shh was downregulated in immature precursor cells, whereas cell type-specific genes were broadly upregulated in mature taste bud cells. Notably, transcription factors driving taste cell type differentiation, such as Pou2f3 , Ascl1 , and Nkx2-2 , were induced, suggesting that tamoxifen activates transcription to promote the differentiation of all cell types in taste buds, rather than activating particular signaling pathways in specific cell types. These findings indicate that tamoxifen rapidly triggers a transcriptional switch from proliferation to differentiation in the circumvallate taste epithelium, highlighting a potential confounding effect in taste research that employs tamoxifen administration.