The sensations of taste, which are divisible into several distinct qualities: sweet, sour, bitter, salty, umami, and possibly fatty, play an important role for accepting or rejecting food and serve to protect us from ingesting harmful substances, but also cause the behavioral preferences to some types of foods. Taste sensations begin with the stimulation of taste receptor cells located in taste buds, small clusters of specialized epithelial cells on the tongue and in the oral cavity. Taste cells release transmitters during gustatory stimulation to stimulate primary afferent sensory fibers that carry the gustatory information to the brain. We have identified several transmitters − including serotonin (5-HT), ATP, norepinephrine (NE), and gamma-aminobutyric acid (GABA) − that are secreted from taste bud cells and uncovered novel mechanisms for transmitter secretion.
A1-2, Micrographs of isolated taste buds immunostained for serotonin (5-HT). Two immunopositive taste cells (red) are visible in this plane of focus. A3, Micrograph of a Fura2-loaded (green) biosensor cell abutted against an isolated taste bud in a living preparation. (adapted from Journal of Neuroscience (2005) 25(4): 843-847; Journal of Neuroscience (2015) 35(37): 12714-12724).
In addition to transmitting gustatory responses to prototypic taste stimuli, taste transmitters may contribute to regulating the function of adjacent taste cells. It is now being recognized there is a significant degree of information processing in the taste buds during gustatory stimulation. We are learning that cell-to-cell communication between neighboring taste cells is a key event before signals are sent to the brain via primary sensory fibers. My lab studies functions of peripheral gustatory sensory organs -- taste buds, using sophisticated anatomical and physiological methods. We apply an innovated technique, including real-time functional calcium imaging with cellular biosensor cells, to detect the secretion of transmitters, and to examine signal processing in taste buds. We used transgenic mice expressing GFP in taste cells. This will allow us to identify specific types of taste cells, and to selectively test transmitter release from taste bud cells. For instance, we, using GAD67-GFP transgenic mice, identified GABA, which inhibits ATP secretion from adjacent Receptor (Type II) cells, secreted from Presynaptic (Type III) cells.
GABA immunostaining of an isolated taste bud from a GAD67-GFP mouse. Many GABA immunopositive taste cells express GFP (thick arrows), but some do not (thin arrows). This latter category may be Type I cells (adapted from PLoS ONE 6(10): e25471).
Sensory signals from the oral cavity are carried to the brain in chemosensory fibers that contribute to chemesthesis, the general chemical sensitivity of the skin and mucus membranes in the oronasal cavities and being perceived as pungency, irritation or heat. Taste perception alterations follow condition changes in the mouth, such as temperature. For instance, the pungency of foods and beverages is likely highly influenced by the temperature at which they are consumed, their acidity, and, for beverages, their carbonation. Furthermore, electrophysiology revealed that taste perception is enhanced as the temperature of food and beverage products increases. The mechanism why/how this occurs is not fully known. Intriguingly, despite the profusion of work identifying mechanisms of chemosensation, little information has been generated regarding irritant–taste interactions. By the use of the cellular biosensor strategy, we reported that calcitonin gene-related peptide (CGRP), which may be released from peripheral axon terminals, modulated taste-evoked ATP secretion from taste buds, which is a key transmitter for communication from taste buds to gustatory nerves. Indeed, unambiguously, our findings suggest that the complex interplay between taste cells and chemosensory neurons may play an important role during the processing of the complex stimuli involving both spicy and tasty components.
Double immunohistochemistry on an isolated taste bud. RCP-immunoreactive (red) taste cells (arrowheads) and SNAP25-immunoreactive (green) Presynaptic (Type III) cells (large arrow) were revealed. Some taste cells exhibit double labeling, suggesting that these Presynaptic (Type III) cells express RCP (small arrows), representing CGRP receptors. (adapted from Journal of Neuroscience (2015) 35(37): 12714-12724).
The characterization of local transmitters and their effects in the taste bud is essential not only for basic understanding of sensory afferent excitation but also for potential clinical applications. These include development of taste modifiers for potential use in management of obesity, compliance in taking medications (particularly in pediatrics), and pharmaceutical development in the context of diminished taste sensation or ageusia (lack of taste) related to age or disease chemotherapy. Indeed, taste perceptions are altered by medications that inadvertently also act on taste bud transmitters. For example, selective serotonin reuptake inhibitors such as, e.g., Prozac - a selective serotonin reuptake inhibitor (SSRI) antidepressant, have known taste side effects. Additionally, our latest findings indicate that Imiquimod, an immune modulator approved for the treatment of basal cell carcinoma, cause abnormal transmitter secretion in taste buds, which may be the basis for taste disturbances that has long been observed in people taking these drugs but has never understood. Nevertheless, my lab plays a pioneering role in exploring the mechanisms of taste reception, and in providing the important information for sensory processing in human health and diseases.
Schematic drawing represents the postulated scenario of CGRP, a putative efferent transmitter, in taste buds. A, Red box represents approximate position of the taste buds in B. B, Numerous CGRP-immunoreactive nerve fibers forming a dense network (large arrows) are seen in the connective tissue core of the papilla, and fine fibers (small arrows) run within, or in close association with, taste buds (areas of dashed lines). C, Chemesthetic stimulation activates sensory afferent fibers that propagate signals centrally (double-headed arrows) and have the ability to release the stored transmitter, CGRP (orange curved arrow). The activation of the CGRP receptors triggers Presynaptic (Type III) cells to secrete 5-HT, which inhibits ATP release from Receptor (Type II) cells (black symbol). (adapted from Journal of Neuroscience (2015) 35(37): 12714-12724).
Science News and Information:
Chemesthesis Affects Taste
Science News and Information:
A Taste of Science
Science News and Information:
Mouse Taste Cells Discriminate Sweet and Sour Tastes by Releasing Neurotransmitters
Education & training
SIUSOM Research Seed Grants (RSG).
AAA (the American Association of Anatomists) Fellows Grant Award Program (FGAP).
Immune gustatory processing: immune responses to drugs shape peripheral taste signals
Taste sensations are considered to be an important factor for detecting and digesting food to maintain good nutrition and leading a healthy lifestyle. Many medications produce altered taste perceptions, which then leads to a direct effect on food-related behaviors. Considering that taste disturbances of patients with have long been observed but never understood, ongoing taste research has identified cellular mechanisms of a variety of drugs that cause taste impairments in cancer patients. These findings facilitate a better understanding of the paradigm that immune responses initiated by drugs can alter taste signal transduction pathways during sensory information processing in taste buds. Inevitably, these findings also may facilitate the development of taste modifiers, which ameliorate taste disturbances associated with the chemotherapy on the compensation of taste sensations for losses in medications.
Taste signals transmitted to the brain are substantially determined by tastants activating taste receptors. But they are also substantially modified by the action of drugs during gustatory information processing in taste buds. The findings that immune responses alter the mechanisms of cellular signaling in taste cells explain the basis for taste dysfunctions of cancer patients that has long been observed but never understood.
There is an increasing interest in causes of taste disorders by researchers striving to improve the health-related quality of life, especially for individuals who are suffering from diseases. Taste plays an important role in food detection and any taste impairments potentially impact food-related behaviors in ways that lead to problems with weight management and poor life quality. Taste deficits often result from medical treatments. For instance, a common side effect of chemotherapy is abnormal taste, which is seen in about 15–55% of cancer sufferers [1,2,3••,4]. With the increase in global consumption of drugs to treat diseases, the incidences of adverse effects caused by drugs, such as xerostomia (dry mouth), hyposalivation, mucositis and taste disorders (particularly the inability to detect basic tastes among patients evaluated by psychophysical methods), escalate [5,6••,7,8, 9, 10,11•]. Inevitably, taste disturbances can have a substantial negative impact on general health by affecting appetite and influencing food choices, and, as a result, can lead to a significant reduction in quality of life.
Taste buds are peripheral taste organs responsible for sensing taste compounds in food and drink and contain taste receptor cells for recognizing sweet, bitter, umami, sour and salty compounds (and possibly, fat). Distinctive turnover mechanisms promote homeostasis in taste buds, with new cells generated from progenitor cells to replace dying cells throughout life [12,13,14•]. Initiation of taste signaling is coordinated through the activation of G protein-coupled receptors (GPCR) or ion channels expressed on corresponding taste receptor cells. These cells then release the main transmitter, ATP, to activate primary afferent sensory fibers that carry the gustatory information to the brain [15, 16, 17]. Intriguingly, despite the important function of taste sensations that guides dietary selection while avoiding toxins and indigestible materials, taste perceptions may be altered by medications [1,2,4,6••,19,11•,18].
In the taste bud, serotonin (5-HT) is identified to be secreted from taste bud cells and exerts negative paracrine feedback, decreasing the secretion of the afferent transmitter, ATP . These results supported the psychophysical demonstration that human taste thresholds were altered by selective 5-HT reuptake inhibitors such as Prozac [18,21]. Conceivably, altered taste perceptions seen in patients with drug-induced taste disturbances may reflect changes in the peripheral taste organs of the gustatory system [3••,6••,22,23••]. The notion that the functions of taste buds are responsible for the process of altering taste thresholds in disease is beginning to be understood.
Fundamental taste research is essential both to understand the source of dysfunctions and to suggest possible therapies. While the causes of taste disorders are multifactorial, defective peripheral taste signaling resulting in the decreased ability to taste certain types of foods is a common pathophysiological contributor to taste disturbances. Numerous pioneering studies have examined loss of taste due to diseases and treatments over the past few years. The modification of taste signals as well as the aberration in homeostasis of taste buds affected by cancer drugs are likely contributors to taste disturbances associated with medications.
Many drugs cause taste disturbances
Pharmaceutical drugs play a key role in protecting and maintaining human health, and restore health of those who have acute and chronic diseases. Common complaints from patients receiving pharmacological treatments are taste impairments [6••,10,11•,24, 25, 26]. The incidences of adverse chemosensory effects from drugs depend on specific medications [6••,11•]. Despite the fragmented literature regarding loss of taste, hypogeusia (decreased taste sensation) and dysgeusia (distorted taste sensation) are most often described in clinical reports and in the scientific literature to classify the severity of taste disturbances (dysfunctions) of patients [6••,10,11•,24,25]. Nevertheless, the incidence of adverse chemosensory effects from drugs is still quite variable, with several factors involved: including individual differences associated with dosage of drugs, drug interactions initiated by using multiple drugs simultaneously, and the adverse sensory properties of the drug itself, such as bitter or metallic tastes [6••]. Of particular note, taste complaints related to drugs with dysgeusia or hypogeusia as a side effect were predominantly reported in patients taking drugs categorized as either immunomodulating or antineoplastic [11•]. Although the recent literature has summarized the potential incidence, dosage correlation, and the potential mechanisms of drug-induced taste disorders [6••,10,11•,25], the exact mechanisms by which drugs disrupt normal taste signaling cascades remain vague. Therefore, to test direct effects of the taste signaling pathways involving systematic drug administration, recent research has focused on aberrant cellular mechanisms in taste bud cells [3••,23••]. These efforts offered insights into whether pharmaceutical drugs alter the authentic cascades of taste signal transduction pathways such as biochemical targets, cell lineages, and transmission of signals.
Immunomodulatory drugs affect taste bud cells
Evidence accumulated over the past decade has highlighted the presence in taste buds, of various molecules involved in innate immune responses. This suggests that defense responses may regulate the structure and functions of taste buds [27, 28, 29, 30]. Inflammatory stimuli derived from pathogens act on taste tissues via Toll-like receptors (TLRs) [28,31]. Activating TLRs upregulates the expression of cytokines such as interferons (IFNs) and tumor necrosis factors (TNFs), which induce apoptosis and cause abnormal cell turnover in taste buds [27,28,31,32]. Since that early work, the list of pro-inflammatory cytokines has been broadened to include lipopolysaccharide (LPS) that mimics bacterial or viral infection . These findings suggest that taste cells directly respond to pathogenic challenges in the oral cavity, and that immune interactions appear to play a role in taste disorders associated with many conditions and diseases. Despite several potential mechanisms of taste disturbances that have been proposed for drug-induced taste disorders, specific mechanisms have yet to be determined. Immune interactions have not been shown directly to influence peripheral taste signals.
It is certainly possible that a medication sometimes causes changes in the body’s ability to recognize taste sensations [1,2,3••,6••,11•,19]. Notably, numerous studies have identified the cellular mechanisms of imiquimod, an immune response modifier approved by the US Food and Drug Administration (FDA) for treating basal cell carcinoma, a common malignant neoplasm worldwide. Imiquimod initiates proinflammatory cytokine pathways during treatments on cancer patients. Specifically, imiquimod acts on target cells via TLR7, a pattern recognition receptor recognizing pathogen-associated molecular patterns (PAMPs) [33, 34, 35, 36], and thus induces the production of proinflammatory cytokines, including IFN-α and TNF-α [33,35,37, 38, 39, 40]. Importantly, patients on imiquimod therapy complain of taste loss . Clinical reports indicate that Imiquimod enters the circulation and generates peak serum concentrations ranging from 0.5–15 μM [41, 42, 43]. This suggests that imiquimod may penetrate into gustatory epithelia containing taste buds. On isolated taste buds, imiquimod acts on taste cells via TLR7 receptors [23••], found mostly on Type II and Type III cells . Imiquimod appears to activate phospholipase C (PLC) or other intracellular molecular signaling pathways either directly or indirectly by binding to a second messenger [44,45], to trigger transmitter secretion, and, as a result, to shape taste signals transmitted to the brain [23••]. Parenthetically, initiation of taste sensations consists of a highly complex set of cell-to-cell interactions within taste buds, via transmitters, before propagating signals to the brain. Reviews by Roper and Chaudhari  and Huang  offer additional details regarding the roles of cell-to-cell interactions on taste.
Alternatively, in spite of the modulation of taste signal transmission attributable to the effect of immune responses, imiquimod may also trigger PLC activation in the Golgi apparatus and nucleus [44,45], in which mRNA export, DNA repair, and gene transcription occur [48,49]. Several reports using in vitro cell culture  and rodent models  have identified nuclear PLCβ, an abundantly represented family of nuclear isozymes which affect G1 progression and thus participate directly in controlling the cell cycle [49,52]. Imiquimod, acting as a potent cell autonomous inhibitor of oncogenic hedgehog signaling, a signaling pathway that transmits information to embryonic cells required for proper cell differentiation , may cause taste changes due to the alteration of intracellular molecular signaling pathways in taste buds. Hence, it is feasible that the interruption of taste cell turnover by cancer drugs results in taste disturbances. This notion has been tested in recent studies, which state that impacted physiology of taste by cancer drugs results in taste changes due to the local effects in taste buds [3••,22]. Figure 1 summarizes the postulated scenarios in the schematic taste bud.
Figure 1. (a) Schematic drawing of the tongue epithelium containing a taste bud. Taste cells are divided into certain morphotypes, which are termed types I (I), II (II), III (III), and taste progenitor cells (also named basal cell, B), originally on the basis of their histologic and ultrastructural characteristics. Red boxes represent approximate positions of the taste bud in B and C. n, nerve fibers. (b) Schematic diagram of a gustatory processing unit shows the pathways of imiquimod within taste buds. Imiquimod freely passed across the membrane of Type III cells and triggered certain PLC isoforms in the nucleus (Nu). Activation of PLC initiated Ca2+ release from internal stores, suggesting IP3 acts on the endoplasmic reticulum (ER) via IP3 receptors (IP3Rs). Imiquimod evoked secretion of 5-HT, which then provided negative feedback onto Type II cells to reduce taste-evoked ATP secretion . Parenthetically, imiquimod may cause taste changes due to the alteration of intracellular oncogenic signaling pathways in taste bud cells. En, endosome. (c) In basal cells, the activated smoothened homolog (SMO) and glioma-associated oncogene homologs (GLI) could be suppressed by vismodegib, these lead to the inhibition of target genes to inhibit the growth and proliferation of progenitor taste cells. In summary, new insights into the immune response explain contributions to taste dysfunctions by adversely affected taste transmission as well as by local effects in taste buds.
Disruption of taste cell renewal alters taste sensations
Nearly all types of basal cell carcinoma are associated with genetic alterations in the hedgehog signaling pathway [1,3••,19,53]. Vismodegib, an antineoplastic agent indicated for the treatment of patients with basal cell carcinoma, has an acceptable and manageable tolerability profile characterized by a number of class-related treatment-emergent adverse events, including muscle spasms, alopecia (baldness), weight loss and asthenia (fatigue) [2,19]. Notably, vismodegib also has the adverse effect of taste disturbances .
With the recognition of taste cell turnover, which was originally believed to maintain the homeostasis of taste papillae via the hedgehog signaling pathway [12,14•], the renewal of taste cells was thought to be the major mechanism underlying vismodegib-induced taste disturbances [3••,22]. Yang et al. [3••] simulated the effect of vismodegib-treated patients using a mouse model and thus identified mechanisms responsible for taste disturbances during medical treatments. Their findings, that blocking the hedgehog signaling pathway causes profound alternations of taste cells expressing biochemical machinery and taste bud structures for taste sensing (Figure 1c), facilitate the understanding of alterations in vismodegib-induced taste disturbances in cancer patients. In addition, the results of a similar type of approach using LDE225, a hedgehog inhibitor, were consistent with the earlier research, which stated that antineoplastic agents result in the disruption of taste progenitor cells that leads to the alteration of taste perceptions . Hence, the notion that the alterations of human taste perceptions related to vismodegib treatments are most likely due to the aberrant taste cell turnover and the integrity of taste bud functions would be congruous. Collectively, these data provide an explanation for the changes of human taste perceptions due to medications, because vismodegib most likely results in similar alterations in human taste buds.
Considering that new drugs are regularly introduced as treatments for diseases, the prevalence of drug-induced taste disorders in medications will likely only escalate. While our understanding of the impact of gustatory mechanisms initiated by immunomodulating or antineoplastic drugs that cause taste disturbances is still in its infancy, recent studies in human and rodents have begun to establish the gustatory correlates, which pave the way for an exciting field of inquiry. In the coming decade, comprehensive investigations on the cellular mechanisms (intracellular signaling, cell lineage, signal transduction pathways, etc.) of taste bud cells affected by pharmaceutical drugs will be important. Such investigations will increase understanding of altered taste perceptions in terms of approaches to investigate taste disturbances from medications.
Recent Publications (since 2005)
Huang, AY (2021) Immune gustatory processing: immune responses to drugs shape peripheral taste signals. Curr Opin Physiol (2021) 20:112-117.
Huang, AY and Wu SY (2020) The Role of Efferent Transmitters in Mouse Taste Bud Signal Transduction. J Anat. 236(1):i88
Huang AY. (2019) Immune responses alter taste perceptions: immunomodulatory drugs shape taste signals during treatments. J Pharmacol Exp Ther. pii: jpet.119.261297. doi: 10.1124/jpet.119.261297.
Huang AY, Wu SY. (2018) Substance P as a putative efferent transmitter mediates GABAergic inhibition in mouse taste buds. Br J Pharmacol.175 (7):1039-1053.
Huang AY, Wu SY. (2016) The effect of imiquimod on taste bud calcium transients and transmitter secretion. Br J Pharmacol. 173(21):3121-3133.
Huang AY, Wu SY. (2016) Isolating Taste Buds and Taste Cells from Vallate Papillae of C57BL/6J Mice for Detecting Transmitter Secretion. Bio-protocol. 6(11):e1824.
Huang AY, Wu SY. (2015) Calcitonin gene-related peptide reduces taste-evoked ATP secretion from mouse taste buds. J Neurosci. 35(37):12714-12724.
Huang AY, Chen MH, Wu SY, Lu KS. (2015) Tight junctions in Gerbil von Ebner's gland: horseradish peroxidase and freeze-fracture studies. Microsc Res Tech. 78(3):213-219.
Rodriguez-Diaz R, Dando R, Huang YA, Berggren P-O, Roper SD, Caicedo A (2012) Real time detection of acetylcholine release from the human endocrine pancreas. Nature Protocols 7(6):1015-1023.
Huang YA, Grant J, Roper SD (2012) Glutamate may be an efferent transmitter that elicits inhibition in mouse taste buds. PLoS ONE 7(1):e30662.
Huang YA, Pereira E, Roper SD (2011) Acid stimulation (sour taste) elicits GABA and serotonin release from mouse taste cells. PLoS ONE 6(10):e25471.
Huang YA, Stone LM, Pereira E, Yang R, Kinnamon JC, Dvoryanchikov G, Chaudhari N, Finger TE, Kinnamon SC, Roper SD (2011) Knocking out P2X receptors reduces transmitter secretion in taste buds. J Neurosci. 31(38): 13654-13661.
Dvoryanchikov G*, Huang YA*, Barro-Soria R, Chaudhari N, Roper SD (2011) GABA, its receptors, and GABAergic inhibition in mouse taste buds. J Neurosci. 31(15):5782-5791. * These authors contributed equally.
Huang YA, Roper SD (2010) Intracellular Ca2+ and TRPM5-mediated membrane depolarization produce ATP secretion from taste receptor cells. J Physiol. 588(13):2343-2350.
Huang YA, Dando RP, Roper SD (2009) Autocrine and paracrine roles of ATP and Serotonin in mouse taste buds. J Neurosci 29(44): 13909-13918.
Huang YA, Maruyama Y, Roper SD (2008) Norepinephrine is co-released with serotonin in mouse taste buds. J. Neurosci. 28(49): 13088-13093.
Huang YA, Maruyama Y, Stimac R, Roper SD (2008) Presynaptic (Type III) cells in mouse taste buds sense sour (acid) taste. J Physiol. 586: 2903-2912.
Huang YA, Maruyama Y, Dvoryanchikov G, Pereira E, Chaudhari N, Roper SD (2007) The role of pannexin 1 hemichannels in ATP release and cell-cell communication in mouse taste buds. Proc Natl Acad Sci. USA. 104(15): 6436-6441.
Huang YA, Maruyama Y, Lu KS, Pereira E, Plonsky I, Baur JE, Roper SD (2005) Mouse taste buds use serotonin as a neurotransmitter. J Neurosci. 25(4): 843-847.
Huang YA, Maruyama Y, Lu KS, Pereira E, Plonsky I, Baur JE, Roper SD (2005) Using biosensors to detect the release of serotonin from taste buds during taste stimulation. Arch Ital Biol. 143: 87-96.
Huang YA, Maruyama Y, Lu KS, Pereira E, Roper SD (2005) Mouse taste buds release serotonin in response to taste stimuli. Chem Senses Suppl 1, 30: i39-i40.