Chemoreceptors are ubiquitous, diverse, and evolutionarily ancient
Every cell is bathed in chemicals. Molecules can be food or poison, or they may serve as signals of communication between cells, organs, or individuals. The ability to recognize and respond to environmental chemicals can allow cells to find nutrients, avoid harm, attract a mate, navigate, or regulate a physiological process. Chemoreception has basic and universal advantages. It is the oldest form of sensory transduction, and it exists in many forms. Chemoreception does not even require a nervous system. Single-celled organisms such as bacteria can recognize and respond to substances in their environment. In the broadest sense, every cell in the human body is chemosensitive, and chemical signaling between cells is the basis for internal communication through endocrine systems and neurotransmission. In this chapter, we restrict ourselves to chemoreception as a sensory system, the interface between the nervous system and the external and internal chemical milieu.
Chemicals reach the human body by oral or nasal ingestion, contact with the skin, or inhalation, and once there, they diffuse or are carried to the surface membranes of receptor cells through the various aqueous fluids of the body (e.g., mucus, saliva, tears, cerebrospinal fluid [CSF], blood plasma). The nervous system constantly monitors these chemical comings and goings with a diverse array of chemosensory receptors. The most familiar of these receptors are the sensory organs of taste (gustation) and smell (olfaction). However, chemoreception is widespread throughout the body. Chemoreceptors in the skin, mucous membranes, respiratory tract, and gut warn against irritating substances, and chemoreceptors in the carotid bodies (see pp. 710–712) measure blood levels of O2, CO2, and [H+].
Taste receptors are modified epithelial cells, whereas olfactory receptors are neurons
The tasks of gustatory and olfactory receptors appear similar at first glance. Both recognize the concentration and identity of dissolved molecules, and they communicate this information to the CNS. In fact, the two systems operate in parallel during eating, and the flavors of most foods are strongly dependent on both taste and smell. The anatomy of the human olfactory system is well adapted to detect odors orthonasally, from the environment, and retronasally, from volatile chemicals released as we chew food. However, the receptor cells of gustation and olfaction are quite different. Olfactory receptors are neurons. Each olfactory cell has small dendrites at one end that are specialized to identify chemical stimuli, and at the other end an axon projects directly into the brain. Taste receptor cells are not neurons but rather modified epithelial cells that synapse onto the axons of sensory neurons that communicate with the CNS.
Taste Receptor Cells
Taste receptors are located mainly on the dorsal surface of the tongue (Fig. 15-1A), concentrated within small but visible projections called papillae (see Fig. 15-1B). Papillae are shaped like ridges, pimples, or mushrooms, and each is a few millimeters in diameter. Each papilla in turn has numerous taste buds (see Fig. 15-1C). One taste bud contains 50 to 150 taste receptor cells, numerous basal and supporting cells that surround the taste cells, plus a set of sensory afferent axons. Most people have 2000 to 5000 taste buds, although exceptional cases range from 500 to 20,000.
FIGURE 15-1 Taste receptors.
The chemically sensitive part of a taste receptor cell is a small apical membrane region near the surface of the tongue. The apical ends have thin extensions called microvilli that project into the taste pore, a small opening on the surface of the tongue where the taste cells are exposed to the contents of the mouth. Taste cells form synapses with the primary sensory axons near the bottom of the taste bud. However, processing may be more complicated than a simple receptor-to-axon relay. Receptor cells also make both electrical and chemical synapses onto some of the basal cells, some basal cells synapse onto the sensory axons, and some type of information-processing circuit may be present within each taste bud itself.
Cells of the taste bud undergo a constant cycle of growth, death, and regeneration. Each taste cell lives about 2 weeks. The turnover of taste cells depends on the influence of the sensory nerve because if the nerve is cut, taste buds degenerate.
Olfactory Receptor Cells
We smell with receptor cells in the thin main olfactory epithelium, which is placed high in the nasal cavity (Fig. 15-2A). We will not discuss several other accessory olfactory systems, including the vomeronasal organ, which primarily detect pheromones. The main olfactory epithelium has three primary cell types: olfactory receptor cells are the site of transduction; support cells are similar to glia and, among other things, help produce mucus; and stem cells, called basal cells, are the source of new receptor cells (see Fig. 15-2B). Olfactory receptors (similar to taste receptors) continually die, regenerate, and grow in a cycle that lasts ~4 to 8 weeks. Olfactory receptor cells are one of the very few types of neurons in the mammalian nervous system that are regularly replaced throughout life.
FIGURE 15-2 Olfactory reception.
As we breathe or sniff, chemical odorants waft through the many folds of the nasal passages. However, to contact the receptor cells, odorants must first dissolve in and diffuse through a thin mucous layer, which has both a viscous and a watery portion. The normal olfactory epithelium exudes a mucous layer 20 to 50 µm thick. Mucus flows constantly and is normally replaced about every 10 minutes. Mucus is a complex, water-based substance containing dissolved glycosaminoglycans (see p. 39); a variety of proteins, including antibodies, odorant-binding proteins, and enzymes; and various salts. The antibodies are critical because olfactory cells offer a direct route for viruses (e.g., rabies) or bacteria to enter the brain. Odorant-binding proteins in the mucus probably facilitate the diffusion of odorants toward and away from the receptors. Enzymes may help clear the mucus of odorants and thus speed recovery of the receptors from transient odors.
Both the absolute size and the receptor density of the olfactory epithelium vary greatly among species, and they help determine olfactory acuity. The surface area of the human olfactory epithelium is only ~10 cm2, but this limited area is enough to detect some odorants at concentrations as low as a few parts per trillion. The olfactory epithelia of some dogs may be over 170 cm2, and dogs have >100 times as many receptors in each square centimeter as humans do. The olfactory acuity of some breeds of dog is legendary and far surpasses that of humans. Dogs can often detect the scent of someone who walked by hours before.
Complex flavors are derived from a few basic types of taste receptors, with contributions from sensory receptors of smell, temperature, texture, and pain
Studies of taste discrimination in humans imply that we can distinguish among 4000 to 10,000 different chemicals with our taste buds. However, behavioral evidence suggests that these discriminations represent only five primary taste qualities: bitter, salty, sweet, and sour plus a primary quality called umami (“delicious” in Japanese). Umami is the taste of certain L-amino acids, epitomized by L-glutamate (monosodium glutamate [MSG], the familiar culinary form). Growing evidence suggests that mammals have a taste system for free fatty acids. Unlike an olfactory receptor cell, which apparently expresses only one receptor type (see p. 358), a taste receptor cell may express several.
In many cases, there is an obvious correlation between the chemistry of tastants (i.e., chemicals being tasted) and the quality of their taste. Most acids taste sour and most salts taste salty. However, for many other tastants, the linkage between taste and chemical structure is not clear. The familiar sugars (e.g., sucrose and fructose) are satisfyingly sweet, but certain proteins (e.g., monellin) and artificial sweeteners (e.g., saccharin and aspartame, the latter of which is made from two amino acids: L-aspartyl-L-phenylalanine methyl ester) are 10,000 to 100,000 times sweeter by weight than these sugars. Bitter substances are also chemically diverse. They include simple ions such as K+ (KCl actually simultaneously evokes both bitter and salty tastes), larger metal ions such as Mg2+, and complex organic molecules such as quinine.
If the tongue has only four or five primary taste qualities available to it, how does it discriminate among the myriad complex flavors that embellish our lives? First, the tongue's response to each tastant reflects distinct proportions of each of the primary taste qualities. In this sense, the taste cells are similar to the photoreceptors of our eyes; with only three different types of color-selective photoreceptive cone cells, we can distinguish a huge palette of colors. Second, the flavor of a tastant is determined not only by its taste but also by its smell. Taste and smell operate in parallel, with information converging in the CNS to aid the important discrimination of foods and poisons. For example, without the aid of olfaction, an onion tastes much like an apple—and both are quite bland. Third, the mouth is filled with other types of sensory receptors that are sensitive to texture, temperature, and pain, and these modalities enhance both the identification and enjoyment of foods. A striking example is the experience of spicy food, which is enjoyable to some but painful to others. The spiciness of hot peppers is generated by the chemical capsaicin, not because of its activation of taste receptor cells but because of its stimulation of heat-sensitive pain receptors in the mouth.
Taste transduction involves many types of molecular signaling systems
The chemicals that we taste have diverse structures, and taste receptors have evolved a variety of mechanisms for transduction. The taste system has adapted many types of membrane-signaling systems to its purposes. Tastants may pass directly through ion channels (salty and sour), bind to and block ion channels (sour) or bind to membrane receptors that activate second-messenger systems, which in turn open or close ion channels (sweet, bitter, and umami). Taste cells use specialized variations of these processes to initiate meaningful signals to the brain.
The receptor potentials of taste cells are usually depolarizing. At least some taste receptor cells can fire action potentials similar to those of neurons, but if the membrane is sufficiently depolarized by whatever means, voltage-gated Ca2+ channels open, and Ca2+ enters the cytoplasm and triggers the release of transmitter molecules. Both the type of neurotransmitter and its mechanism of its release differ by cell type. Sour and salty taste cells use a conventional Ca2+-triggered vesicular mechanism to release serotonin onto gustatory axons, whereas sweet-, bitter-, and umami-selective taste cells use a Ca2+-triggered nonvesicular mechanism to release ATP as their transmitter.
Evidence from mice suggests that each taste receptor cell responds to only one of the five basic taste modalities. Each of the taste receptor cells is, in turn, hard-wired to the CNS to convey a particular taste quality. For example, if we genetically alter a mouse to express a bitter receptor in sweet taste receptor cells, the mouse—naturally attracted to sweet tastants—will be attracted to bitter tastants, which now will taste sweet.
The complex diversities of taste transduction are not yet fully understood. The following is a summary of the best-understood transduction processes for the five primary taste qualities in mammals (Fig. 15-3).
FIGURE 15-3 Cellular basis of taste transduction. Although, for convenience, we show two taste modalities in A and three in B, individual taste cells do not express more than one of the taste mechanisms. ER, endoplasmic reticulum; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C.
The most common salty-tasting chemical is NaCl, or table salt. The taste of salt is mainly the taste of the cation Na+. At relatively low concentrations (10 to 150 mM), NaCl is usually attractive to animals; at higher concentrations it is increasingly aversive. Completely different mechanisms transduce low and high [NaCl]. Salt-sensitive taste cells detect low [NaCl] using the epithelial Na+ channel ENaC (see Fig. 15-3A), which is blocked by the drug amiloride (see pp. 758–759). These cells also have an amiloride-insensitive cation channel that contributes to salt transduction. Unlike the Na+ channel that generates action potentials in excitable cells, the taste channels are relatively insensitive to voltage and stay open at rest. However, transduction of the [Na+] in a mouthful of food is somewhat analogous to the behavior of a neuron during the upstroke of an action potential. When [Na+] rises outside the receptor cell, the gradient for Na+ across the membrane becomes steeper, Na+ diffuses down its electrochemical gradient (i.e., it flows into the cell), and the resultant inward current causes the membrane to depolarize to a new voltage. Neurons depolarize during their action potential by increasing Na+ conductance at a fixed Na+ gradient (see Fig. 7-4). In contrast, Na+-sensitive taste cells depolarize by increasing the Na+ gradient at a fixed Na+ permeability. The resultant graded depolarization of the taste cell is defined as its receptor potential.
High concentrations of NaCl and other salts taste bad to humans, and animals normally avoid ingesting them. In mice, high [NaCl] activates bitter and sour taste cells, although the mechanism is not clear. Bitter and sour tastants normally trigger avoidance, and the offensive qualities of high [NaCl] seem to stimulate the same avoidance pathways.
Anions may affect the taste of salts by modulating the saltiness of the cation or by adding a taste of their own. NaCl tastes saltier than Na acetate, perhaps because the larger an anion is, the more it inhibits the salty taste of the cation. Na saccharin is sweet because the anion saccharin activates sweetness receptors; it is not salty because Na+ is present at a very low concentration.
Sourness is evoked by protons (H+ ions). Acidity may affect taste receptors in several ways (see Fig. 15-3A). Sour taste cells express a type of acid-sensitive channel complex comprising the nonselective cation channel TRPP3 (see Table 6-2, family No. 5; also known as PKD2L1) and PKD1L3; both are related to proteins implicated in polycystic kidney disease. Selective elimination of taste cells expressing TRPP3 abolishes the gustatory response to acidic stimuli. Protons may also affect the gating of other cation-selective channels such as the hyperpolarization-activated channels (HCNs; see Table 6-2, family No. 3) and the acid-sensitive channels (ASICs; see Table 6-2, family No. 14) that would lead to depolarization of taste cells.
Carbonated liquids evoke interesting sensations. Carbonation—high levels of dissolved CO2—can activate the gustatory, olfactory, and somatosensory neurons. Sour taste cells seem to be critical for the gustatory features of CO2. These cells express an extracellular form of carbonic anhydrase, CA IV, an enzyme that rapidly catalyzes the conversion of CO2 into and H+. Thus, in the presence of CA IV, increased [CO2] leads to the production of H+ that may act on effectors in the receptor cells to mediate the taste of carbonation. Consistent with this, mountain climbers taking acetazolamide, the carbonic anhydrase inhibitor, to treat acute mountain sickness (see p. 1232) have reported that beer and soda taste disappointingly flat.
Sweetness is sensed when molecules bind to specific receptor sites on the taste cell membrane and activate a cascade of second messengers (see Fig. 15-3B). Two families of taste receptor genes—the T1R family and T2R family—seem to account for sweet, bitter, and umami transduction. These taste receptors are GPCRs (see pp. 51–66), and all use the same basic second-messenger pathway. In the case of sweetness transduction, the tastant (e.g., a sugar molecule) binds to a taste receptor that consists of a dimer of T1R2 and T1R3 GPCRs. The activated receptor then activates a G protein that stimulates phospholipase C (PLC), which in turn increases its production of the messenger inositol 1,4,5-trisphosphate (IP3; see p. 58). IP3 triggers the release of Ca2+ from internal stores, and the rise in [Ca2+]i then activates a relatively nonselective cation channel called TRPM5 (see Table 6-2, family No. 5), which is specific for taste cells. Opening TRPM5 depolarizes the taste cell, triggering the release of neurotransmitter onto the primary gustatory axon (see Fig. 15-3B). The sweet receptor complex—the T1R2/T1R3 dimer—is broadly sensitive to sweet-tasting substances. It appears that sweet-sensing taste cells do not express receptors for either bitter or umami. N15-1
Diversity of Sweet and Umami Taste Reception
Contributed by Barry Connors
Taste receptors are quite diverse among species, and this leads to considerably different taste preferences that may be adaptations to each animal's ecological niche. Preferences for sweet substances are strongly determined by the T1R subunits. Some species, notably cats and some other carnivores, lack a functional T1R2 gene and are indifferent to compounds that humans consider sweet. Mice are usually uninterested in aspartame, the artificial sweetener favored by people, but introducing the human T1R2 gene into the taste cells of a mouse makes them responsive to aspartame. Some mammalian species (including all types of bats) lack a functional T1R1 receptor and presumably cannot taste amino acids.
Bitterness often warns of poison. Perhaps because poisons are so chemically diverse, we have about 25 different types of bitter receptors to sense them. These are dimers of GPCRs in the T2R family. Animals are not very good at distinguishing between different bitter substances, probably because each bitter taste cell expresses most or all of the 25 T2Rs. It may be more important to recognize that something is bitter, and potentially poisonous, than it is to recognize precisely what type of poison it may be. Bitter compounds trigger responses at much lower concentrations (i.e., they have much binding higher affinities) than sweet and umami substances. Stimulation of the T2Rs activates a second-messenger pathway that is apparently identical to the one that sweet receptors activate: G proteins, PLC, IP3, [Ca2+]i increase, and TRPM5 channel opening. We do not confuse the tastes of sweet and bitter substances because even though they trigger similar signaling systems, each transduction cascade occurs within a specific sweet or bitter taste cell. Moreover, each taste cell makes synaptic contact with a different primary gustatory axon that leads into the CNS.
Amino acids are critical nutrients that are vital as an energy source and for construction of proteins. Probably as a consequence, many amino acids taste good, although some taste bitter. The umami taste, which we know well from some Asian restaurants, is triggered by a mechanism very similar to that for sweet taste. The umami receptor is a heterodimer comprising two members of the T1R family, T1R1 and T1R3. Note that the umami and sweet receptors share T1R3. The taste for some L-amino acids seems to depend on T1R1 because mice that lack it are unable to discriminate glutamate and other amino acids, although they retain their ability to detect sweet substances. N15-1 The umami receptor activates the same signaling mechanisms that sweet and bitter receptors do: G proteins, PLC, IP3, [Ca2+]i increase, and TRPM5 channel opening. Again, by isolating the umami receptors in taste cells that do not also express sweet and bitter receptors, the CNS can distinguish the various tastes from one another by somehow knowing which taste cell connects to a particular gustatory axon.
Olfactory transduction involves specific receptors, G protein–coupled signaling, and a cyclic nucleotide–gated ion channel
Our ability to smell chemicals is better developed than our ability to taste them. By one estimate, we can smell >400,000 different substances. Interestingly, ~80% of them smell unpleasant. As with taste, it seems likely that smell evolved to serve important protective functions, such as warning us away from harmful substances. The main and accessory olfactory systems can also detect pheromones, volatile chemicals used by individuals of a species to trigger stereotyped behavioral or hormonal changes. In some species, olfaction even allows one individual to detect whether others are dangerous or ill. With the ability to discriminate so many different smells, you might also expect many different types of transduction mechanisms, as in the taste system. In fact, the main olfactory receptors probably use only one second-messenger mechanism. Figure 15-4 summarizes the chain of events in the main olfactory receptor cells that leads to action potentials in the olfactory nerve (i.e., cranial nerve I [CN I]).
Step 1: The odorant binds to a specific olfactory receptor protein in the cell membrane of a cilium of an olfactory receptor cell.
Step 2: Receptor activation stimulates a heterotrimeric G protein called Golf (see Table 3-2).
Step 3: The α subunit of Golf in turn activates an adenylyl cyclase (specifically, ACIII), which produces cAMP.
Step 4: The cAMP binds to a CNG cyclic nucleotide–gated cation channel (see Table 6-2, family No. 4).
Step 5: Opening of this channel increases permeability to Na+, K+, and Ca2+.
Step 6: The net inward current leads to membrane depolarization and increased [Ca2+]i.
Step 7: The increased [Ca2+]i opens Ca2+-activated Cl− channels called anoctamin2 (ANO2; see Table 6-2, family No. 17). Opening of these channels produces more depolarization because of the relatively high [Cl−]iof olfactory receptor neurons.
Step 8: If the receptor potential exceeds the threshold, it triggers action potentials in the soma that travel down the axon and into the brain.
FIGURE 15-4 Cellular mechanism of odor sensation.
All this molecular machinery, with the exception of the action potential mechanism, is squeezed into the thin cilia of olfactory receptor cells. Moreover, additional modulatory schemes also branch from this basic pathway.
Olfactory receptor cells express a huge family of receptor proteins; in fact, olfactory receptor genes are the largest family of mammalian genes known! Their discovery in the early 1990s earned Linda Buck and Richard Axel the 2004 Nobel Prize in Physiology or Medicine. N15-2 Rodents have >1000 different olfactory receptor genes. Humans have ~350 genes that encode functional receptor proteins. This family of olfactory receptor proteins belongs to the superfamily of GPCRs (see pp. 51–52) that also includes the phototransduction protein rhodopsin and the taste receptors for sweet, bitter, and umami described above as well as the receptors for a wide variety of neurotransmitters.
Richard Axel and Linda Buck
For more information about Richard Axel and Linda Buck and the work that led to their Nobel Prize, visit http://nobelprize.org/nobel_prizes/medicine/laureates/2004/ (accessed December 2014).
The extracellular surfaces of olfactory receptor proteins have odorant binding sites, each slightly different from the others. Presumably, each receptor protein can bind only certain types of odorants; therefore, some degree of selectivity is conferred to different olfactory receptor cells. Remarkably, each receptor cell seems to express only a single gene of the 1000 different odorant receptor genes in rodents. Thus, 1000 different types of olfactory receptor cells are present, each identified by the one receptor gene that it expresses. Because each odorant may activate a large proportion of the different receptor types, the central olfactory system's task is to decode the patterns of receptor cell activity that signals the identity of each smell.
The structure of the olfactory cAMP-gated channel is closely related to that of the light-activated channel in photoreceptors of the retina, which is normally gated by an increase in [cGMP]i. The olfactory channel and the photoreceptor channel almost certainly evolved from one ancestral CNG channel, just as the olfactory receptor and photoreceptor proteins probably evolved from an ancestral receptor with seven membrane-spanning segments.
Termination of the olfactory response occurs when odorants diffuse away, scavenger enzymes in the mucous layer break them down, or cAMP in the receptor cell activates other signaling pathways that end the transduction process.