Bitter taste receptors in the reproductive system: Function and therapeutic implications.

Type 2 taste receptors (TAS2Rs), traditionally known for their role in bitter taste perception, are present in diverse reproductive tissues of both sexes. This review explores our current understanding of TAS2R functions with a particular focus on reproductive health. In males, TAS2Rs are believed to play potential roles in processes such as sperm chemotaxis and male fertility. Genetic insights from mouse models and human polymorphism studies provide some evidence for their contribution to male infertility. In female reproduction, it is speculated that TAS2Rs influence the ovarian milieu, shaping the functions of granulosa and cumulus cells and their interactions with oocytes. In the uterus, TAS2Rs contribute to uterine relaxation and hold potential as therapeutic targets for preventing preterm birth. In the placenta, they are proposed to function as vigilant sentinels, responding to infection and potentially modulating mechanisms of fetal protection. In the cervix and vagina, their analogous functions to those in other extraoral tissues suggest a potential role in infection defense. In addition, TAS2Rs exhibit altered expression patterns that profoundly affect cancer cell proliferation and apoptosis in reproductive cancers. Notably, TAS2R agonists show promise in inducing apoptosis and overcoming chemoresistance in these malignancies. Despite these advances, challenges remain, including a lack of genetic and functional studies. The application of techniques such as single-cell RNA sequencing and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated endonuclease 9 gene editing could provide deeper insights into TAS2Rs in reproduction, paving the way for novel therapeutic strategies for reproductive disorders.

Neuroscience of taste: unlocking the human taste code.

Since antiquity human taste has been divided into 4-5 taste qualities. We realized in the early 1970s that taste qualities vary between species and that the sense of taste in species closer to humans such as primates should show a higher fidelity to human taste qualities than non-primates (Brouwer et al. in J Physiol 337:240, 1983). Here we present summary results of behavioral and single taste fiber recordings from the distant South American marmoset, through the Old World rhesus monkey to chimpanzee, the phylogenetically closest species to humans. Our data show that in these species taste is transmitted in labelled-lines to the CNS, so that when receptors on taste bud cells are stimulated, the cell sends action potentials through single taste nerve fibers to the CNS where they create taste, whose quality depends on the cortical area stimulated. In human, the taste qualites include, but are perhaps not limited to sweet, sour, salty, bitter and umami. Stimulation of cortical taste areas combined with inputs from internal organs, olfaction, vision, memory etc. leads to a choice to accept or reject intake of a compound. The labelled-line organization of taste is another example of Müller's law of specific nerve energy, joining other somatic senses such as vision (Sperry in J Neurophysiol 8:15-28, 1945), olfaction (Ngai et al. in Cell 72:657-666, 1993), touch, temperature and pain to mention a few.

Characteristics of A-type voltage-gated K+ currents expressed on sour-sensing type III taste receptor cells in mice.

Sour taste is detected by type III taste receptor cells that generate membrane depolarization with action potentials in response to HCl applied to the apical membranes. The shape of action potentials in type III cells exhibits larger afterhyperpolarization due to activation of transient A-type voltage-gated K+ currents. Although action potentials play an important role in neurotransmitter release, the electrophysiological features of A-type K+ currents in taste buds remain unclear. Here, we examined the electrophysiological properties of A-type K+ currents in mouse fungiform taste bud cells using in-situ whole-cell patch clamping. Type III cells were identified with SNAP-25 immunoreactivity and/or electrophysiological features of voltage-gated currents. Type III cells expressed A-type K+ currents which were completely inhibited by 10 mM TEA, whereas IP3R3-immunoreactive type II cells did not. The half-maximal activation and steady-state inactivation of A-type K+ currents were 17.9 ± 4.5 (n = 17) and - 11.0 ± 5.7 (n = 17) mV, respectively, which are similar to the features of Kv3.3 and Kv3.4 channels (transient and high voltage-activated K+ channels). The recovery from inactivation was well fitted with a double exponential equation; the fast and slow time constants were 6.4 ± 0.6 ms and 0.76 ± 0.26 s (n = 6), respectively. RT-PCR experiments suggest that Kv3.3 and Kv3.4 mRNAs were detected at the taste bud level, but not at single-cell levels. As the phosphorylation of Kv3.3 and Kv3.4 channels generally leads to the modulation of cell excitability, neuromodulator-mediated A-type K+ channel phosphorylation likely affects the signal transduction of taste.

The effect of bariatric surgery on the expression of gastrointestinal taste receptors: A systematic review.

Gastrointestinal nutrient sensing via taste receptors may contribute to weight loss, metabolic improvements, and a reduced preference for sweet and fatty foods following bariatric surgery. This review aimed to investigate the effect of bariatric surgery on the expression of oral and post-oral gastrointestinal taste receptors and associations between taste receptor alterations and clinical outcomes of bariatric surgery. A systematic review was conducted to capture data from both human and animal studies on changes in the expression of taste receptors in oral or post-oral gastrointestinal tissue following any type of bariatric surgery. Databases searched included Medline, Embase, Emcare, APA PsychInfo, Cochrane Library, and CINAHL. Two human and 21 animal studies were included. Bariatric surgery alters the quantity of many sweet, umami, and fatty acid taste receptors in the gastrointestinal tract. Changes to the expression of sweet and amino acid receptors occur most often in intestinal segments surgically repositioned more proximally, such as the alimentary limb after gastric bypass. Conversely, changes to fatty acid receptors were observed more frequently in the colon than in the small intestine. Significant heterogeneity in the methodology of included studies limited conclusions regarding the direction of change in taste receptor expression induced by bariatric surgeries. Few studies have investigated associations between taste receptor expression and clinical outcomes of bariatric surgery. As such, future studies should look to investigate the relationship between bariatric surgery-induced changes to gut taste receptor expression and function and the impact of surgery on taste preferences, food palatability, and eating behaviour.Registration code in PROSPERO: CRD42022313992.

Give-and-take of gustation: the interplay between gustatory neurons and taste buds.

Mammalian taste buds are highly regenerative and can restore themselves after normal wear and tear of the lingual epithelium or following physical and chemical insults, including burns, chemotherapy, and nerve injury. This is due to the continual proliferation, differentiation, and maturation of taste progenitor cells, which then must reconnect with peripheral gustatory neurons to relay taste signals to the brain. The turnover and re-establishment of peripheral taste synapses are vital to maintain this complex sensory system. Over the past several decades, the signal transduction and neurotransmitter release mechanisms within taste cells have been well delineated. However, the complex dynamics between synaptic partners in the tongue (taste cell and gustatory neuron) are only partially understood. In this review, we highlight recent findings that have improved our understanding of the mechanisms governing connectivity and signaling within the taste bud and the still-unresolved questions regarding the complex interactions between taste cells and gustatory neurons.

Cyclophosphamide induces the loss of taste bud innervation in mice.

Many common chemotherapeutics produce disruptions in the sense of taste which can lead to loss of appetite, nutritional imbalance, and reduced quality of life, especially if taste loss persists after treatment ends. Cyclophosphamide (CYP), an alkylating chemotherapeutic agent, affects taste sensitivity through its cytotoxic effects on mature taste receptor cells (TRCs) and on taste progenitor cell populations, retarding the capacity to replace TRCs. Mechanistic studies have focused primarily on taste cells, however, taste signaling requires communication between TRCs and the gustatory nerve fibers that innervate them. Here, we evaluate cyclophosphamide's effects on the peripheral gustatory nerve fibers that innervate the taste buds. Following histological analysis of tongue tissues, we find that CYP reduces innervation within the fungiform and circumvallates taste buds within 4 days after administration. To better understand the dynamics of the denervation process, we used 2-photon intravital imaging to visualize the peripheral gustatory nerve fibers within individual fungiform taste buds up to 20 days after CYP treatment. We find that gustatory fibers retract from the taste bud properly but are maintained within the central papilla core. These data indicate that in addition to TRCs, gustatory nerve fibers are also affected by CYP treatment. Because the connectivity between TRCs and gustatory neurons must be re-established for proper function, gustatory fibers should continue to be included in future studies to understand the mechanisms leading to chemotherapy-induced persistent taste loss.

Ultrastructural localization of calcium homeostasis modulator 1 in mouse taste buds.

Taste receptor cells are morphologically classified as types II and III. Type II cells form a unique type of synapses referred to as channel synapses where calcium homeostasis modulator 1 (CALHM1) together with CALHM3 forms voltage-gated channels that release the neurotransmitter, adenosine triphosphate (ATP). To validate the proposed structural model of channel synapses, the ultrastructural localization of CALHM1 in type II cells of both fungiform and circumvallate taste buds was examined. A monoclonal antibody against CALHM1 was developed and its localization was evaluated via immunofluorescence and immunoelectron microscopy using the immunogold-silver labeling technique. CALHM1 was detected as puncta using immunofluorescence and along the presynaptic membrane of channel synapses facing atypical mitochondria, which provide ATP, by immunoelectron microscopy. In addition, it was detected along the plasma membrane lined by subsurface cisternae at sites apposed to afferent nerve fibers. Our results support the validity of a previously proposed structural model for channel synapses and provide insights into the function of subsurface cisternae whose function in taste receptor cells is unknown. We also examined the localization of CALHM1 in hybrid synapses of type III cells, which are conventional chemical synapses accompanied by mitochondria similar to atypical mitochondria of channel synapses. CALHM1 was not detected in the six hybrid synapses examined using immunoelectron microscopy. We further performed double immunolabeling for CALHM1 and Bassoon, which is detected as puncta corresponding to conventional vesicular synapses in type III cells. Our observations suggest that at least some, and probably most, hybrid synapses are not accompanied by CALHM1.

The Obese Taste Bud study: Objectives and study design.

AIMS: Taste modifies eating behaviour, impacting body weight and potentially obesity development. The Obese Taste Bud (OTB) Study is a prospective cohort study launched in 2020 at the University of Leipzig Obesity Centre in cooperation with the HI-MAG Institute. OTB will test the hypothesis that taste cell homeostasis and taste perception are linked to obesity. Here, we provide the study design, data collection process and baseline characteristics. MATERIALS AND METHODS: Participants presenting overweight, obesity or normal weight undergo taste and smell tests, anthropometric, and taste bud density (TBD) assessment on Day 1. Information on physical and mental health, eating behaviour, physical activity, and dental hygiene are obtained, while biomaterial (saliva, tongue swap, blood) is collected in the fasted state. Further blood samples are taken during a glucose tolerance test. A stool sample is collected at home prior to Day 2, on which a taste bud biopsy follows dental examination. A subsample undergoes functional magnetic resonance imaging while exposed to eating-related cognitive tasks. Follow-up investigations after conventional weight loss interventions and bariatric surgery will be included. RESULTS: Initial results show that glycated haemoglobin levels and age are negatively associated with TBD, while an unfavourable metabolic profile, current dieting, and vegan diet are related to taste perception. Olfactory function negatively correlates with age and high-density lipoprotein cholesterol. CONCLUSION: Initial findings suggest that metabolic alterations are relevant for taste and smell function and TBD. By combining omics data from collected biomaterial with physiological, metabolic and psychological data related to taste perception and eating behaviour, the OTB study aims to strengthen our understanding of taste perception in obesity.

Does presbygeusia really exist? An updated narrative review.

This review critically assessed the existence of presbygeusia, i.e., the impairment in taste perception occurring in the elderly, as a natural part of the aging process and its potential clinical implications. Several factors might contribute to age-related taste alterations (TAs), including structural changes in taste buds, alterations in saliva composition, central nervous system changes, and oral microbiota dysbiosis. A comprehensive literature review was conducted to disentangle the effects of age from those of the several age-related diseases or conditions promoting TAs. Most of the included studies reported TAs in healthy elderly people, suggesting that presbygeusia is a relatively frequent condition associated with age-related changes in the absence of pathological conditions. However, the impact of TAs on dietary preferences and food choices among the elderly seems to be less relevant when compared to other factors, such as cultural, psychological, and social influences. In conclusion, presbygeusia exists even in the absence of comorbidities or drug side effects, but its impact on dietary choices in the elderly is likely modest.

Antillean manatee (Trichechus manatus manatus Linnaeus, 1758) Tongue Morphology and Adaptive Herbivorous Implications.

Morphological study of the tongue is an interesting way of understanding evolutionary processes associated with feeding habits. Therefore, the aim of the present study was to describe the tongue morphology of the Antillean manatee and to understand possible morphological relationships with its way of capturing food. Macroscopic dissections and light and scanning electron microscopy analyses of seven manatee tongues were performed. The tongue in Antillean manatees is a muscular and robust organ, divided into apex, body, and root. It is firmly adhered to the floor of the oral cavity. Lingual papillae were distributed over the entire tongue surface. They were identified as filiform papillae concentrated in the apex. Fungiform papillae were present on the apex and lateral regions. Foliate papillae were located on the dorsolateral portion of the root. Lentiform papillae were located across the dorsal tongue surface. The mucosa was lined by a keratinized stratified squamous epithelium presenting compound tubuloacinar glands and taste buds in the foliate papillae. The tongue of the Antillean manatee is similar to other Sirenia species, both of which share a completely herbivorous diet.

Piezo 1 and Piezo 2 in the Chemosensory Organs of Zebrafish (Danio rerio).

The ion channels Piezo 1 and Piezo 2 have been identified as membrane mechano-proteins. Studying mechanosensitive channels in chemosensory organs could help in understanding the mechanisms by which these channels operate, offering new therapeutic targets for various disorders. This study investigates the expression patterns of Piezo proteins in zebrafish chemosensory organs. For the first time, Piezo protein expression in adult zebrafish chemosensory organs is reported. In the olfactory epithelium, Piezo 1 immunolabels kappe neurons, microvillous cells, and crypt neurons, while Calretinin is expressed in ciliated sensory cells. The lack of overlap between Piezo 1 and Calretinin confirms Piezo 1's specificity for kappe neurons, microvillous cells, and crypt neurons. Piezo 2 shows intense immunoreactivity in kappe neurons, one-ciliated sensory cells, and multi-ciliated sensory cells, with overlapping Calretinin expression, indicating its olfactory neuron nature. In taste buds, Piezo 1 immunolabels Merkel-like cells at the bases of cutaneous and pharyngeal taste buds and the light and dark cells of cutaneous and oral taste buds. It also marks the dark cells of pharyngeal taste buds and support cells in oral taste buds. Piezo 2 is found in the light and dark cells of cutaneous and oral taste buds and isolated chemosensory cells. These findings provide new insights into the distribution of Piezo channels in zebrafish chemosensory organs, enhancing our understanding of their sensory processing and potential therapeutic applications.

Mechanisms and Functions of Sweet Reception in Oral and Extraoral Organs.

The oral detection of sugars relies on two types of receptor systems. The first is the G-protein-coupled receptor TAS1R2/TAS1R3. When activated, this receptor triggers a downstream signaling cascade involving gustducin, phospholipase Cß2 (PLCß2), and transient receptor potential channel M5 (TRPM5). The second type of receptor is the glucose transporter. When glucose enters the cell via this transporter, it is metabolized to produce ATP. This ATP inhibits the opening of KATP channels, leading to cell depolarization. Beside these receptor systems, sweet-sensitive taste cells have mechanisms to regulate their sensitivity to sweet substances based on internal and external states of the body. Sweet taste receptors are not limited to the oral cavity; they are also present in extraoral organs such as the gastrointestinal tract, pancreas, and brain. These extraoral sweet receptors are involved in various functions, including glucose absorption, insulin release, sugar preference, and food intake, contributing to the maintenance of energy homeostasis. Additionally, sweet receptors may have unique roles in certain organs like the trachea and bone. This review summarizes past and recent studies on sweet receptor systems, exploring the molecular mechanisms and physiological functions of sweet (sugar) detection in both oral and extraoral organs.

A quantitative study of the development of taste pores in mice.

OBJECTIVES: This study determined the early development of taste buds by observing the changes in the three-dimensional structures of taste pores and microvilli in the circumvallate papillae (CVP) of mice, from pre- and postnatal stages to the adult stages. METHODS: Fragments of mouse CVP tissue were collected on embryonic day (E) 18 and postnatal days (P) 0, 3, 6, 7, 14, 21, 28, and 56. The surfaces of the tissue fragments located pore apertures via scanning electron microscopy, and the sizes of the CVP and maximum diameters of the pores were estimated from the recorded images. Likewise, changes in the structures of the epithelium around the pore aperture and microvilli protruding from the pores were examined. RESULTS: The size of the CVP exhibited a linear increase with age from E18 to P56. The epithelium around the pore aperture demonstrated changes to form microridges, indicating a characteristic pattern during CVP development. The size of the pore aperture also increased with age from E18 to P56. Furthermore, an increase in the number of pores with protruding microvilli was observed at the base of the epithelial trench. A significant positive correlation was observed between the maximum diameter of the pore and the size of the CVP. CONCLUSIONS: The expansion in the lateral view of the CVP was associated with the developmental stage from E18 to P56, suggesting that the growth of the CVP leads to the opening and enlargement of the taste pores with microvillus projections during these stages.

[Research progress in functional regeneration methods and mechanisms of taste buds].

Gustation is one of the most important human senses. Taste dysfunctions, which may be due to aging, tongue cancer surgery, radiotherapy and chemotherapy, affect life quality. That is why the need for taste bud regeneration has received more attention. At present, research on development and renewal of taste cells provides a basis for taste bud regeneration; molecular mechanisms related to taste bud regeneration are being continuously uncoverd, aiding in the identification of more accurate targets for therapy. New methods such as nerve regeneration, tissue engineering, and cytokine therapy have emerged. The author reviews the mechanism and the latest methods of taste bud regeneration of lingual epithelium, aiming to open new horizions for the prevention and treatment of gustatory diseases, and provide theoretical references for its regeneration.

Back to the water: Tongue morphology associated to contrasting lifestyles in two Andean frogs of the genus Telmatobius.

The evolution of the tongue in tetrapods is associated with feeding in the terrestrial environment. This study analyzes the tongue morphology of two closely related frog species, Telmatobius oxycephalus and T. rubigo, which exhibit contrasting feeding mechanisms. Telmatobius oxycephalus, a semi-aquatic species, relies on its tongue to capture terrestrial prey whereas T. rubigo, a secondarily aquatic species, uses suction feeding not involving the tongue. Through anatomical, histological and scanning electron microscopy analyses, we revealed remarkable differences in tongue morphology between these species. Telmatobius oxycephalus exhibits a well-developed tongue whose dorsal epithelium has numerous and slender filiform papillae. The epithelial cells of the papillae are protruded and have a complex array of microridges. In contrast, T. rubigo possesses a reduced tongue with flat and less numerous filiform papillae. The epithelial cells are completely flat and lack microridges. These findings highlight the remarkable adaptability of lingual morphology in Telmatobius to respond to the contrasting ecological niches and prey capture mechanisms. This study sheds light on the relationship between tongue shape and the different functional demands, contributing to our understanding of the evolution of prey capture mechanisms in amphibians.

Neural circuits for taste sensation.

The sense of taste arises from the detection of chemicals in food by taste buds, the peripheral cellular detectors for taste. Although numerous studies have extensively investigated taste buds, research on neural circuits from primary taste neurons innervating taste buds to the central nervous system has only recently begun owing to recent advancements in neuroscience research tools. This minireview focuses primarily on recent reports utilizing advanced neurogenetic tools across relevant brain regions.

Morphological adaptation of the tongue of okapi (Okapia johnstoni Artiodactyla, Giraffidae)-Anatomy, histology, and ultrastructure.

The aim of this study was to describe the morphology of the tongue of the okapi, and to compare the results with other ruminants including browsers, intermediates and grazers. The material was collected post-mortem from two animals from a Zoological Garden. The structure of the okapi tongue, focusing of the shape of the tongue, lingual surface, its papillae and lingual glands, was examined using gross morphology, light and polarized microscopy, and by scanning electron microscopy. The okapi tongue was characterized by dark pigmentation on the lingual dorsum (except lingual torus) and on the whole ventral surface. Two types of filiform papillae were observed, with additional, even 6-8 projections at their base. The round fungiform papillae were present at a higher density, up to 16/cm2, on the ventro-lateral area of the lingual apex. Round and elongate vallate papillae were arranged in two parallel lines between the body and root of the tongue. Numerous taste buds were detected within the epithelium of their vallum, while fungiform papillae had sparse taste buds. A lack of foliate papillae was noted. Very small conical papillae, some lenticular in shape, were present on the lingual torus. Thick collagen type I fibers were dominant over collagen type III fibers in the connective tissue of the lingual papillae. The mucous acini units were dominant among lingual glands, indicating that the secretion of okapi lingual glands was mostly mucous. In many aspects, the tongue of okapi resembles the tongue of other ruminants. The specific lingual shape and lingual surface, together with the lingual glands, support the processing of plant food, such as young and soft leaves. Although okapi tongue is characterized by smaller conical papillae compared to other ruminants, its high number of vallate papillae is similar that found in other browsers, intermediate and grazers. Thus the number of gustatory papillae rather indicates that this feature is not related to the type of feeding.

VirtuousPocketome: a computational tool for screening protein-ligand complexes to identify similar binding sites.

Protein residues within binding pockets play a critical role in determining the range of ligands that can interact with a protein, influencing its structure and function. Identifying structural similarities in proteins offers valuable insights into their function and activation mechanisms, aiding in predicting protein-ligand interactions, anticipating off-target effects, and facilitating the development of therapeutic agents. Numerous computational methods assessing global or local similarity in protein cavities have emerged, but their utilization is impeded by complexity, impractical automation for amino acid pattern searches, and an inability to evaluate the dynamics of scrutinized protein-ligand systems. Here, we present a general, automatic and unbiased computational pipeline, named VirtuousPocketome, aimed at screening huge databases of proteins for similar binding pockets starting from an interested protein-ligand complex. We demonstrate the pipeline's potential by exploring a recently-solved human bitter taste receptor, i.e. the TAS2R46, complexed with strychnine. We pinpointed 145 proteins sharing similar binding sites compared to the analysed bitter taste receptor and the enrichment analysis highlighted the related biological processes, molecular functions and cellular components. This work represents the foundation for future studies aimed at understanding the effective role of tastants outside the gustatory system: this could pave the way towards the rationalization of the diet as a supplement to standard pharmacological treatments and the design of novel tastants-inspired compounds to target other proteins involved in specific diseases or disorders. The proposed pipeline is publicly accessible, can be applied to any protein-ligand complex, and could be expanded to screen any database of protein structures.