What are gustatory receptors and where are they present?

Abstract

Taste receptors are proteins that recognize taste stimuli of various types, thereby functioning as the initial component in the process of sensing and discriminating ingested material. Taste stimuli can be categorized as belonging to one of at least five classes, comprising qualities perceived by humans as sweet, salty, sour, bitter, and umami (the savory taste of l-amino acids such as glutamate). Mammalian taste receptors that respond to sweet, bitter, and umami stimuli have been identified and functionally characterized. These receptors are expressed on the apical membranes of taste receptor cells (TRCs) that extend into the oral cavity. The receptor-stimulus-binding event initiates a transduction cascade in TRCs, leading to cell depolarization and neurotransmitter release onto afferent nerve fibers, and ultimately propagation of sensory information to taste processing areas in the central nervous system.

4.09.3.2.1 Orphan receptors Tas1R1 and Tas1R2

The taste receptors Tas1R1 and Tas1R2 were first identified in taste cell-specific libraries (Hoon, M. A. et al., 1999). It was originally proposed that mTas1R2 might be a bitter-responsive receptor and that mTas1R1 might be a sweet-responsive taste receptor; the rationale being that Tas1R1 is expressed at the front of the tongue (which is sometimes thought to be more sensitive to sweet) and that Tas1R1 gene maps nearer to the sac locus at the distal end of mouse chromosome 4 (Hoon, M. A. et al., 1999). While it is true that both Tas1R1 and Tas1R2 map to the distal end of mouse chromosome 4, refined mapping studies indicated that Tas1R1 and Tas1R2 are several centimorgans away from the sac locus, much too far to be the sac gene itself (Li, X. et al., 2001).

The taste cell-specific expression of Tas1R1 and Tas1R2 suggested that both receptors might play roles in taste transduction. In situ hybridization showed that Tas1R1 and Tas1R2 have different expression patterns in rat taste tissue: rTas1R1 is localized to geschmackstreifen (taste stripe) and fungiform papillae, and rTas1R2 is localized primarily to circumvallate and foliate papillae. The significance of this regional expression pattern is unclear, since it does not correspond to any known pattern of tastant sensitivity in rodents (Lindemann, B., 1999; Sako, N. et al., 2000). Prior to the discovery of Tas1R3, the function of the Tas1R1 and Tas1R2 orphan receptors could not be studied in heterologous cells because as was later shown, Tas1R1 and Tas1R2 form obligate heterodimers with Tas1R3 to function, hindering identification of their natural ligands.

Synopsis

Taste receptors beyond the taste system can be found in several locations defined as extraoral taste receptors. Taste receptors were discovered in the taste system and named after it, but discoveries in the last two decades open the debate that these are more chemical receptors with more broad distribution than the taste system. Extraoral taste receptors are in both mucosae and internal organs and cover functions that go from detecting and fighting infection to relaxing airways, but many more functions will be discovered in the next few years. The functional link to health and disease makes the extraoral taste receptors a new powerful pharmacological target for the treatment of several diseases and conditions.

Taste

Taste receptors in the tongue send information via the 7th and 9th cranial nerves to reach the nucleus of the solitary tract in the hindbrain. The nucleus of the solitary tract projects to a specific gustatory nucleus in the thalamus, and from there to the insular cortex. The taste receptors in the tongue have only a limited range of perception (salt, sweet, sour, bitter, savory, and piquant) and much of what we call taste is actually based on extra information from our olfactory system.

Taste sensation

The basic sense of taste is relatively crude, because the taste receptors can only distinguish a limited number of characteristics of food. We therefore rely on our sense of smell to judge the quality of what we eat. As we chew or swallow, the odors of the food reach the olfactory nerve endings and supplement the information from the taste receptors on the tongue.

Taste and Olfactory Receptors Turn Over Regularly

Taste and olfactory receptors line epithelia that are regularly exposed to potentially noxious materials. Because of this exposure, most epithelial cells are regularly sloughed off and replaced with new cells. The same is true for the taste and olfactory receptors. Olfactory receptors turn over every 4–8 weeks. Since the taste receptors are modified epithelial cells, this ability is not surprising. Olfactory cells, on the other hand, are true neurons whose cell bodies are located in the olfactory mucosa and which project axons directly to the olfactory bulb in the brain. Nevertheless, these olfactory neurons are continually replaced throughout life. Basal cells in the olfactory epithelium undergo mitosis to produce new olfactory receptor cells that must grow new axons into the olfactory bulb and make new connections there.

26.3.2.1 Neurotransmitters in the Taste Bud

TRCs express multiple neurotransmitters and neurotransmitter receptors across selective subsets of cells within the bud. These neurotransmitter pathways include serotonin (5-HT),187,188 norepinephrine (NE),189–191 acetylcholine (ACh),192–195 γ-amino butyric acid (GABA),196,197 and adenosine trisphosphate (ATP).40,198,199 Also, neuropeptides such as cholecystokinin (CCK),202 neuropeptide Y (NPY),203 and glucagon-like peptide-1 (GLP-1)204 participate within the bud. These signaling agents and their cognate receptors are expressed in autocrine and paracrine patterns across the bud, delineating hardwired pathways for cell-to-cell communication.

Ironically, one of the first demonstrations of cell-to-cell communication in the taste bud was the demonstration that TRCs respond to serotonin, the neurotransmitter assumed to be important in neural transmission.205 Serotonin is expressed in a subset of type III cells in the taste buds of a large number of species, including mouse, rat, rabbit, and monkey.206–211 Reports that TRCs respond to serotonergic stimulation were unexpected given its putative role as a neurotransmitter with the afferent fiber.212 In rat posterior TRCs, application of exogenous serotonin results in inhibition of a calcium-activated potassium current205 and of the voltage-dependent sodium current.213 Both effects were mimicked by agonists of the 5-HT1A receptor subtype. Subsequently, TRCs of a number of species have been documented to respond to serotonin.205,213–217 Serotonin and the 5-HT1A receptor are expressed in a paracrine manner,187 suggesting that release of serotonin from type III cells acts to inhibit a subset of neighboring cells. Serotonin is released in response to multiple tastant qualities in mouse taste buds,188 presumably due to communication of type II cells with type III cells. The role of serotonin in gustatory processing is essentially unknown. Since its action is inhibitory, serotonin may provide a negative feedback pathway onto type II cells that limits ATP release.

The primary route of communication of the TRC with the afferent nerve fiber, previously supposed to be serotonergic, was discovered to be purinergic.40 The most striking evidence in support of this conclusion is the observation that double-knockout mice for the P2X2 and P2X3 receptor genes are essentially ageusic. With some exceptions, these animals lost behavioral and electrophysiological responses to all taste qualities, such as sweet, sour, bitter, salty, and umami. ATP is released from TRCs in response to tastant stimulation198 in a calcium-independent but voltage-dependent manner. This release likely occurs through connexin or pannexin hemichannels198,199 and thus does not require a classic synaptic structure. TRCs that release ATP are type II cells and express type II markers such as gustducin, PLCβ2, and TRPM5. ATP release also signals other TRCs in the bud in addition to the afferent nerve. TRCs express P2Y receptors.200,201 ATP release from type II cells may not only stimulate afferent nerve fibers, but additionally stimulate type III cells via cell-to-cell communication by activation of P2Y receptors.201 This stimulation may then result in serotonin release from these cells.199

GABA is another neurotransmitter that likely functions as an endogenous inhibitory route of cell-to-cell communication. In the rat, GABA, GABAA, and GABAB receptors, and the membrane transporter GAT3 are expressed in subsets of TRCs.196,197 GABA is expressed in a subset of type II cells, based on overlapping expression with type II cell markers, gustducin and SNAP-25, and exclusion from the type III cell markers, NCAM or PGP 9.5.196 The expression of GABAA receptors is assumed to be autocrine, whereas GABAB receptors have been demonstrated to be paracrine. Studies with patch-clamp recordings confirmed that receptor activation with exogenously applied GABA or receptor-specific agonists resulted in inhibitory actions. Since GABA cells (marked by GAD expression) overlap with gustducin, they must overlap with T1R and/or T2R receptors. Similarly, that GABAB receptors do not overlap with gustducin suggests that stimulation with one taste quality (e.g., bitter) could inhibit TRC expression receptors of a different taste quality (e.g., sweet). This arrangement could serve as a peripheral basis for mixture suppression. In contrast to the expression patterns observed in the rat, GABA expression is concluded to occur in type III cells in the mouse.218 The mouse also expresses GABAA and GABAB receptors in type II and type III cells, but its autocrine or paracrine relationships have yet to be elucidated.219

NE has long been suspected as a possible neurotransmitter in the taste bud, although the understanding of its role remains rudimentary. The earliest suggestions that subsets of TRCs in rabbits and mice could be adrenergic came from histofluorescence studies.220–225 Some studies also suggested that there may be adrenergic fibers that surround the taste bud.226–229 In the mammalian system, the first physiological studies implicating a role of NE in the bud came with the demonstration that chloride currents were enhanced by its exogenous application.191 Subsequently, it was shown that some TRCs are adrenergic and that TRCs express both α- and β-adrenoceptors.189 In fact, virtually all adrenoceptors are expressed in the bud (α1A, α1B, α1D, α2A, 2B, 2C, β1, and β2) in a complex overlapping pattern that implies both presynaptic and postsynaptic distributions.230 Dopamine-β-hydroxylase (DβH), the synthetic enzyme for NE, is expressed in rat and frog TRCs,230,231 but not in mice.190 Phenyl-n-methyl transferase is expressed in rat taste buds suggesting that epinephrine may also participate in taste bud cell-to-cell communication. TRCs additionally express other molecules involved in the transporting, inactivation, and packaging of NE, which include norepinephrine transporter (NET), catechol-O-methyltransferase, monoamine oxidase-A, vesicular monoamine transporter (1 and 2), chromogranin A, and β-arrestin.190,230 In mouse TRCs, NE is released from type III cells in response to acid stimulation232 and a small subset of these cells coreleased both serotonin and NE. Since these cells were isolated using GFP expression driven by a GAD promoter, these data further suggest that this group of cells may co-store GABA, serotonin, and NE. In rat TRCs, activation of α-receptors acts to elevate intracellular calcium levels, while activation of β-receptors produces an inhibition of outward potassium currents.189 Both responses would result in overall excitation of the cell.

A role for NE in the peripheral gustatory system has also been suggested in humans. Human taste thresholds are modulated by NE; enhancing NE levels (using a NE reuptake inhibitor) notably reduced bitter and sour thresholds.233 Hence, NE may increase the sensitivity of the gustatory system to these qualities. This observation is in agreement with findings in rodents that NE acts as an excitatory modulator in the gustatory system that is involved in more than one taste quality. Further understanding of the role of adrenergic transmission in the taste bud will require more detailed information about the pattern of adrenoceptor expression in the bud and physiological consequences of their excitation.

Taste Receptors or “Taste Buds”

Taste receptors are modified elongated epithelial cells found throughout the oral cavity on hard and soft palates, tonsils, pharynx, and epiglottis, but they are most numerous on the tongue. Taste pores are openings in the epithelium for chemical substances to enter, and regional gene expression surrounding taste buds regulates their formation and is partially controlled by innervating nerves.140 Peripheral sensory innervation is though branches of three cranial nerves: facial (VII), glossopharyngeal (IX), and vagal (X). Of the four morphologically distinct types of lingual papillae, only three bear taste receptors: the fungiform, foliate, and circumvallate papillae.13,141

Specialized taste cells first appear in the human fetus at 7 to 8 weeks' gestation and are morphologically mature at 13 to 15 weeks.142 Chemicals in the amniotic fluid may stimulate fetal taste receptors. The fetus begins to swallow amniotic fluid episodically at the 12th week of gestation,143 and by term even anencephalic fetuses can swallow 200 to 760 mL per day.144 Amniotic fluid contains glucose, fructose, lactic acid, pyruvic acid, citric acid, fatty acids, phospholipids, creatinine, urea, uric acid, various amino acids, polypeptides, proteins, and salts.145 The composition may change during gestation and is altered by fetal urination into this fluid.146

Traditionally, four fundamental tastes are identified: salty, bitter, sweet, and sour. More recently it was discovered that the artificial flavor enhancer monosodium glutamate (MSG; umami) also has specific glutamate receptors and hence must be regarded as a fifth fundamental taste that can be detected even in the newborn.147,148 None of these specific tastes are segregated within the gustatory nuclei of the brain stem or in the cortical gustatory regions. Nevertheless, each taste is detected by dedicated taste receptor cells in the taste buds, and there is fine selectivity in taste preference in ganglion cells and specific transfer of taste information between taste cells and the brain.149

IV.I. Tasting

Taste receptor cells in the mouth, tongue, palate, and pharynx are innervated by axons of afferent neurons with cell bodies located in peripheral ganglia associated with facial, glossopharyngeal, and vagal cranial nerves. Centrally directed axons enter the medulla oblongata and synapse with secondary sensory neurons in the rostral portion of the nucleus of the tractus solitarius (Fig. 2c). Ascending axons of these secondary cells synapse in the parabrachial nucleus (pontine taste center) and also possibly project directly to the thalamus. Neurons in the parabrachial nucleus have extensive rostral connections with forebrain regions, including the amygdala and taste areas of the cortex.

Oral anatomy

Although taste receptors are located throughout the oral cavity, many are clustered on taste papillae located on the dorsal surface of the tongue. The most plentiful of these are fungiform papillae, which are mushroom-shaped structures distributed over the anterior tongue. Foliate papillae consist of folds located on the margins of the tongue, while circumvallate papillae are large, circular structures forming a chevron near the back of the tongue. A fourth type of papilla, filiform, is widely distributed over the dorsal surface, but houses no taste buds.

Taste buds are rosebud shaped groups of cells (Smith and Margolskee, 2001). Each bud contains about 100 cells, some of which are taste receptor cells. Tastants (molecules of products in solution) pass through a small pore at the top of the taste bud and contact finger-like projections from the taste receptor cells. These projections (microvilli) contain receptor-proteins. Receptors for sweet, savory (umami), and bitter (see below) are probably expressed in different subsets of taste receptor cells, although a given cell may express multiple types of bitter receptors (Zhao et al., 2003; Mueller et al., 2005; Breslin and Huang, 2006). Accordingly, a given taste receptor cell may respond to a number of different compounds, but those compounds will tend to signal the same taste quality (though this picture may change when sour and salty receptors are identified).

Abstract

Taste receptor cells sense various chemical compounds in foods and transmit these signals through gustatory nerve fibers to the central nervous system. These sensory signals are vitally important for life; they provide information about which prospective foods are nutritious and warnings as to those that are noxious. Recent studies have revealed the involvement of multifarious bioactive peptides, many of which are primarily identified organs such as the gastrointestinal tract, in the modulation of taste responses. These peptides affect peripheral taste responsiveness of animals and play important roles in the regulation of feeding behavior and the maintenance of homeostasis. In this chapter, we discuss the various functions of peptide signaling in the peripheral taste system.