Common Sense about Taste: From Mammals to Insects
2009; Cell Press; Volume: 139; Issue: 2 Linguagem: Inglês
10.1016/j.cell.2009.10.001
ISSN1097-4172
AutoresDavid A. Yarmolinsky, Charles S. Zuker, Nicholas J. P. Ryba,
Tópico(s)Neurobiology and Insect Physiology Research
ResumoThe sense of taste is a specialized chemosensory system dedicated to the evaluation of food and drink. Despite the fact that vertebrates and insects have independently evolved distinct anatomic and molecular pathways for taste sensation, there are clear parallels in the organization and coding logic between the two systems. There is now persuasive evidence that tastant quality is mediated by labeled lines, whereby distinct and strictly segregated populations of taste receptor cells encode each of the taste qualities. The sense of taste is a specialized chemosensory system dedicated to the evaluation of food and drink. Despite the fact that vertebrates and insects have independently evolved distinct anatomic and molecular pathways for taste sensation, there are clear parallels in the organization and coding logic between the two systems. There is now persuasive evidence that tastant quality is mediated by labeled lines, whereby distinct and strictly segregated populations of taste receptor cells encode each of the taste qualities. Unlike touch, vision, audition, or olfaction, which function in diverse behavioral contexts, the sense of taste has evolved to serve as a dominant regulator and driver of feeding behavior. Gustatory systems detect nutritionally relevant and harmful compounds in food and trigger innate behaviors leading to acceptance or rejection of potential food sources. Taste is therefore a powerful system in which to ask the question, how is sensory input transformed and distributed to evoke a specific behavioral output? A first step in this endeavor is to define how tastant identity and concentration are translated into patterns of activity by primary receptor cells. This Review describes recent progress on this problem and illustrates how dissimilar organisms have converged on a common strategy for the encoding of taste information. Humans, and probably most mammals, categorize taste stimuli into a small palette of qualities (Lindemann, 2001Lindemann B. Receptors and transduction in taste.Nature. 2001; 413: 219-225Crossref PubMed Scopus (485) Google Scholar, Chandrashekar et al., 2006Chandrashekar J. Hoon M.A. Ryba N.J. Zuker C.S. The receptors and cells for mammalian taste.Nature. 2006; 444: 288-294Crossref PubMed Scopus (1041) Google Scholar). The tastes of sweet, bitter, sour, and salty are familiar to all, while umami, a savory taste elicited by certain L-amino acids (Ikeda, 1909Ikeda K. On a new seasoning.J. Tokyo Chem. Soc. 1909; 30: 820-836Google Scholar), constitutes a fifth “primary” taste modality. Umami and sweet are “good” tastes that promote consumption of nutritive food (such as the building blocks for protein synthesis and energy), whereas bitter and sour are “bad” tastes that alert the organism to toxins and low pH, promoting rejection of foods containing harmful substances (for instance, noxious plants or spoiled or unripe fruits). Salt can taste either “good” or “bad” to us and be attractive or repulsive to mice, depending both on the concentration of sodium and on the physiological needs of the taster (Lindemann, 2001Lindemann B. Receptors and transduction in taste.Nature. 2001; 413: 219-225Crossref PubMed Scopus (485) Google Scholar, Bachmanov et al., 2002Bachmanov A.A. Beauchamp G.K. Tordoff M.G. Voluntary consumption of NaCl, KCl, CaCl2, and NH4Cl solutions by 28 mouse strains.Behav. Genet. 2002; 32: 445-457Crossref PubMed Scopus (62) Google Scholar). The modest breadth of this repertoire, together with the innate relationship of quality to hedonic valence and behavioral response, imply that the task of the taste system is not “subtle discrimination,” or connoisseurship, but rather to drive binary decisions about whether to consume or reject a potential food item. Although animals, particularly humans, may acquire a taste for an initially unattractive tastant (for example, coffee), taste preferences are at the outset innate (that is, genetically encoded). For example, naive rodents will avidly consume sweet solutions over water and always choose water over bitter, sour, and concentrated salt solutions. In addition the function of the taste system is greatly impacted by olfaction, texture, and the internal state of the organism. Indeed, our own taste perceptions are richly modulated by hunger, satiety, emotion, and expectation. Appropriate to being gatekeepers for feeding behavior, taste receptor cells (TRCs) are found in the mouth and are concentrated on surfaces of the tongue and palate (Figure 1). TRCs are organized into taste buds, ovoid structures typically composed of 50–100 cells (Delay et al., 1986Delay R.J. Kinnamon J.C. Roper S.D. Ultrastructure of mouse vallate taste buds: II. Cell types and cell lineage.J. Comp. Neurol. 1986; 253: 242-252Crossref PubMed Scopus (148) Google Scholar, Kinnamon et al., 1993Kinnamon J.C. Henzler D.M. Royer S.M. HVEM ultrastructural analysis of mouse fungiform taste buds, cell types, and associated synapses.Microsc. Res. Tech. 1993; 26: 142-156Crossref PubMed Scopus (44) Google Scholar, Lindemann, 2001Lindemann B. Receptors and transduction in taste.Nature. 2001; 413: 219-225Crossref PubMed Scopus (485) Google Scholar). On the tongue, taste buds are housed within epithelial structures termed papillae, of which there are three types: (1) dozens of taste buds are distributed across the anterior surface of the tongue in fungiform papillae, (2) hundreds are located in the trenches of circumvallate papillae at the back, and (3) dozens to hundreds more localize to the sides of the tongue in foliate papillae. Many isolated taste buds are also distributed on the soft palate. Taste signals from the fungiform taste buds and palate are transmitted to neurons in the geniculate ganglion via the chorda tympani and greater superficial petrosal nerve, respectively, whereas the circumvallate and foliate papillae are innervated primarily by the glossopharyngeal nerve, composed of fibers initiating from the petrosal ganglion (Figure 1). Notably, TRCs actively regenerate during adult life, with taste cells living an average of only 2 weeks before dying and being replaced by newly born cells (Lindemann, 2001Lindemann B. Receptors and transduction in taste.Nature. 2001; 413: 219-225Crossref PubMed Scopus (485) Google Scholar); this poses the interesting challenge of ensuring that the correct newly born TRC connects to the appropriate afferent nerve fibers. Taste information from sensory ganglia converges onto the rostral portion of the nucleus of the solitary tract in the brainstem, from where it is routed through the parabrachial nucleus in mice or directly to the ventral posteromedial nucleus of the thalamus in primates. From the thalamus, projections connect to the primary gustatory cortex in the insula. Local projections from the nucleus of the solitary tract (NST) within the brainstem mediate low-level (i.e., noncortical) behavioral responses, such as salivation and gaping induced by bitter taste (Spector and Travers, 2005Spector A.C. Travers S.P. The representation of taste quality in the mammalian nervous system.Behav. Cogn. Neurosci. Rev. 2005; 4: 143-191Crossref PubMed Scopus (128) Google Scholar). How are tastants detected on the tongue? The pre-Socratic philosopher Democritus suggested that the different taste qualities are generated by the mechanical action of variously shaped “atoms” on the surface of the tongue. This is not too far from our current understanding that taste perception is initiated by the physical interaction of tastant molecules with specific receptor proteins located at the surface of TRCs (Figure 2). The attractive tastes, sweet and umami, are sensed by heterodimeric G protein-coupled receptors (GPCRs) assembled by the combinatorial arrangement of T1R1, T1R2, and T1R3 subunits (Nelson et al., 2001Nelson G. Hoon M.A. Chandrashekar J. Zhang Y. Ryba N.J. Zuker C.S. Mammalian sweet taste receptors.Cell. 2001; 106: 381-390Abstract Full Text Full Text PDF PubMed Scopus (1299) Google Scholar, Li et al., 2002Li X. Staszewski L. Xu H. Durick K. Zoller M. Adler E. Human receptors for sweet and umami taste.Proc. Natl. Acad. Sci. USA. 2002; 99: 4692-4696Crossref PubMed Scopus (1049) Google Scholar, Nelson et al., 2002Nelson G. Chandrashekar J. Hoon M.A. Feng L. Zhao G. Ryba N.J. Zuker C.S. An amino-acid taste receptor.Nature. 2002; 416: 199-202Crossref PubMed Scopus (1085) Google Scholar, Zhao et al., 2003Zhao G.Q. Zhang Y. Hoon M.A. Chandrashekar J. Erlenbach I. Ryba N.J. Zuker C.S. The receptors for mammalian sweet and umami taste.Cell. 2003; 115: 255-266Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar). The key role of these receptors in mediating mammalian sweet and umami taste was uncovered from a range of studies, including heterologous expression in cell-based assays (Nelson et al., 2001Nelson G. Hoon M.A. Chandrashekar J. Zhang Y. Ryba N.J. Zuker C.S. Mammalian sweet taste receptors.Cell. 2001; 106: 381-390Abstract Full Text Full Text PDF PubMed Scopus (1299) Google Scholar, Nelson et al., 2002Nelson G. Chandrashekar J. Hoon M.A. Feng L. Zhao G. Ryba N.J. Zuker C.S. An amino-acid taste receptor.Nature. 2002; 416: 199-202Crossref PubMed Scopus (1085) Google Scholar, Li et al., 2002Li X. Staszewski L. Xu H. Durick K. Zoller M. Adler E. Human receptors for sweet and umami taste.Proc. Natl. Acad. Sci. USA. 2002; 99: 4692-4696Crossref PubMed Scopus (1049) Google Scholar) and the engineering of mice with ablated or genetically altered T1R subunits (Damak et al., 2003Damak S. Rong M. Yasumatsu K. Kokrashvili Z. Varadarajan V. Zou S. Jiang P. Ninomiya Y. Margolskee R.F. Detection of sweet and umami taste in the absence of taste receptor T1r3.Science. 2003; 301: 850-853Crossref PubMed Scopus (451) Google Scholar, Zhao et al., 2003Zhao G.Q. Zhang Y. Hoon M.A. Chandrashekar J. Erlenbach I. Ryba N.J. Zuker C.S. The receptors for mammalian sweet and umami taste.Cell. 2003; 115: 255-266Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar). Together, these studies validated T1R1+3 (a heteromeric receptor composed of the T1R1 and T1R3 subunits) as the mammalian umami receptor (Li et al., 2002Li X. Staszewski L. Xu H. Durick K. Zoller M. Adler E. Human receptors for sweet and umami taste.Proc. Natl. Acad. Sci. USA. 2002; 99: 4692-4696Crossref PubMed Scopus (1049) Google Scholar, Nelson et al., 2002Nelson G. Chandrashekar J. Hoon M.A. Feng L. Zhao G. Ryba N.J. Zuker C.S. An amino-acid taste receptor.Nature. 2002; 416: 199-202Crossref PubMed Scopus (1085) Google Scholar, Zhao et al., 2003Zhao G.Q. Zhang Y. Hoon M.A. Chandrashekar J. Erlenbach I. Ryba N.J. Zuker C.S. The receptors for mammalian sweet and umami taste.Cell. 2003; 115: 255-266Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar) and T1R2+3 as the mammalian sweet taste receptor (Nelson et al., 2001Nelson G. Hoon M.A. Chandrashekar J. Zhang Y. Ryba N.J. Zuker C.S. Mammalian sweet taste receptors.Cell. 2001; 106: 381-390Abstract Full Text Full Text PDF PubMed Scopus (1299) Google Scholar, Li et al., 2002Li X. Staszewski L. Xu H. Durick K. Zoller M. Adler E. Human receptors for sweet and umami taste.Proc. Natl. Acad. Sci. USA. 2002; 99: 4692-4696Crossref PubMed Scopus (1049) Google Scholar, Damak et al., 2003Damak S. Rong M. Yasumatsu K. Kokrashvili Z. Varadarajan V. Zou S. Jiang P. Ninomiya Y. Margolskee R.F. Detection of sweet and umami taste in the absence of taste receptor T1r3.Science. 2003; 301: 850-853Crossref PubMed Scopus (451) Google Scholar, Zhao et al., 2003Zhao G.Q. Zhang Y. Hoon M.A. Chandrashekar J. Erlenbach I. Ryba N.J. Zuker C.S. The receptors for mammalian sweet and umami taste.Cell. 2003; 115: 255-266Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar). The T1R2+3 sweet receptor recognizes simple sugars, a wide range of artificial sweeteners, D-amino acids, and even intensely sweet proteins (Figure 2). How does a single receptor accommodate this broad range of tastants? Recent structure-function studies have begun to dissect the fine-grained details of the T1R receptor complexes and identified several discrete sites on each of the three subunits that participate in ligand binding (Cui et al., 2006Cui M. Jiang P. Maillet E. Max M. Margolskee R.F. Osman R. The heterodimeric sweet taste receptor has multiple potential ligand binding sites.Curr. Pharm. Des. 2006; 12: 4591-4600Crossref PubMed Scopus (125) Google Scholar, Jiang et al., 2004Jiang P. Ji Q. Liu Z. Snyder L.A. Benard L.M. Margolskee R.F. Max M. The cysteine-rich region of T1R3 determines responses to intensely sweet proteins.J. Biol. Chem. 2004; 279: 45068-45075Crossref PubMed Scopus (235) Google Scholar, Jiang et al., 2005Jiang P. Cui M. Zhao B. Snyder L.A. Benard L.M. Osman R. Max M. Margolskee R.F. Identification of the cyclamate interaction site within the transmembrane domain of the human sweet taste receptor subunit T1R3.J. Biol. Chem. 2005; 280: 34296-34305Crossref PubMed Scopus (169) Google Scholar, Winnig et al., 2007Winnig M. Bufe B. Kratochwil N.A. Slack J.P. Meyerhof W. The binding site for neohesperidin dihydrochalcone at the human sweet taste receptor.BMC Struct. Biol. 2007; 7: 66Crossref PubMed Scopus (96) Google Scholar); the presence of multiple sites in each receptor complex may help explain their remarkable breadth of tuning. Mammalian taste receptors show markedly more sequence divergence between species than do typical GPCRs (Adler et al., 2000Adler E. Hoon M.A. Mueller K.L. Chandrashekar J. Ryba N.J. Zuker C.S. A novel family of mammalian taste receptors.Cell. 2000; 100: 693-702Abstract Full Text Full Text PDF PubMed Scopus (990) Google Scholar, Nelson et al., 2001Nelson G. Hoon M.A. Chandrashekar J. Zhang Y. Ryba N.J. Zuker C.S. Mammalian sweet taste receptors.Cell. 2001; 106: 381-390Abstract Full Text Full Text PDF PubMed Scopus (1299) Google Scholar). This diversity is the substrate for functional differences reflecting the adaptation of different species to distinct ecological niches and diet. For example, mice and humans display a number of differences in the range of compounds stimulating sweet and umami taste. Umami is strongly stimulated in humans only by L-Glutamate (MSG) and L-Aspartate, whereas mice display robust attraction and neural responses to the majority of L-amino acids (Iwasaki et al., 1985Iwasaki K. Kasahara T. Sato M. Gustatory effectiveness of amino acids in mice: behavioral and neurophysiological studies.Physiol. Behav. 1985; 34: 531-542Crossref PubMed Scopus (40) Google Scholar, Nelson et al., 2002Nelson G. Chandrashekar J. Hoon M.A. Feng L. Zhao G. Ryba N.J. Zuker C.S. An amino-acid taste receptor.Nature. 2002; 416: 199-202Crossref PubMed Scopus (1085) Google Scholar, Zhao et al., 2003Zhao G.Q. Zhang Y. Hoon M.A. Chandrashekar J. Erlenbach I. Ryba N.J. Zuker C.S. The receptors for mammalian sweet and umami taste.Cell. 2003; 115: 255-266Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar). Similarly, humans taste as sweet several compounds to which mice are indifferent (e.g., aspartame; Nelson et al., 2001Nelson G. Hoon M.A. Chandrashekar J. Zhang Y. Ryba N.J. Zuker C.S. Mammalian sweet taste receptors.Cell. 2001; 106: 381-390Abstract Full Text Full Text PDF PubMed Scopus (1299) Google Scholar). Notably, these differences in selectivity are perfectly matched by the tuning of the respective T1R subunits, such that exchanging T1R components between the human and mouse receptors generate the corresponding altered taste selectivity both in cell-based assays and in vivo (Nelson et al., 2001Nelson G. Hoon M.A. Chandrashekar J. Zhang Y. Ryba N.J. Zuker C.S. Mammalian sweet taste receptors.Cell. 2001; 106: 381-390Abstract Full Text Full Text PDF PubMed Scopus (1299) Google Scholar, Nelson et al., 2002Nelson G. Chandrashekar J. Hoon M.A. Feng L. Zhao G. Ryba N.J. Zuker C.S. An amino-acid taste receptor.Nature. 2002; 416: 199-202Crossref PubMed Scopus (1085) Google Scholar, Li et al., 2002Li X. Staszewski L. Xu H. Durick K. Zoller M. Adler E. Human receptors for sweet and umami taste.Proc. Natl. Acad. Sci. USA. 2002; 99: 4692-4696Crossref PubMed Scopus (1049) Google Scholar, Zhao et al., 2003Zhao G.Q. Zhang Y. Hoon M.A. Chandrashekar J. Erlenbach I. Ryba N.J. Zuker C.S. The receptors for mammalian sweet and umami taste.Cell. 2003; 115: 255-266Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar). This strict correlation between receptor function and behavioral selectivity and sensitivity across species strongly implies that T1R receptors are a major determining factor in species-specific taste preferences. Indeed, two extreme examples illustrate this principle: (1) introduction of the human T1R2 gene into mice humanizes sweet taste preferences (Zhao et al., 2003Zhao G.Q. Zhang Y. Hoon M.A. Chandrashekar J. Erlenbach I. Ryba N.J. Zuker C.S. The receptors for mammalian sweet and umami taste.Cell. 2003; 115: 255-266Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar), and (2) the Felidae family acquired a loss-of-function mutation in the T1R2 gene early in their evolution and have consequently loss all sweet taste; this nicely explains the behavioral indifference of all cats to sugars (Li et al., 2005Li X. Li W. Wang H. Cao J. Maehashi K. Huang L. Bachmanov A.A. Reed D.R. Legrand-Defretin V. Beauchamp G.K. et al.Pseudogenization of a sweet-receptor gene accounts for cats' indifference toward sugar.PLoS Genet. 2005; 1: e3https://doi.org/10.1371/journal.pgen.0010003Crossref PubMed Scopus (175) Google Scholar). Orthologs of the three T1Rs are present in the genomes of all vertebrates thus far examined. T1Rs have not been identified in any invertebrate species, including the chordates amphioxus and Ciona intestinalis. Importantly, all members of the T1R family are present in fish, where they also function as heteromeric receptors (Oike et al., 2007Oike H. Nagai T. Furuyama A. Okada S. Aihara Y. Ishimaru Y. Marui T. Matsumoto I. Misaka T. Abe K. Characterization of ligands for fish taste receptors.J. Neurosci. 2007; 27: 5584-5592Crossref PubMed Scopus (111) Google Scholar, Yasuoka and Abe, 2009Yasuoka A. Abe K. Gustation in fish: Search for prototype of taste perception.Results Probl. Cell Differ. 2009; 47: 239-255Crossref PubMed Scopus (29) Google Scholar). However, fish T1R2+3 responds to L-amino acids rather than prototypical sweet tastants (Oike et al., 2007Oike H. Nagai T. Furuyama A. Okada S. Aihara Y. Ishimaru Y. Marui T. Matsumoto I. Misaka T. Abe K. Characterization of ligands for fish taste receptors.J. Neurosci. 2007; 27: 5584-5592Crossref PubMed Scopus (111) Google Scholar, Yasuoka and Abe, 2009Yasuoka A. Abe K. Gustation in fish: Search for prototype of taste perception.Results Probl. Cell Differ. 2009; 47: 239-255Crossref PubMed Scopus (29) Google Scholar). This suggests that the mammalian T1R2+3 complex was remodeled to recognize sugars at some point during the transition of vertebrates from oceans to land. The role of sweet and umami taste is to help identify food sources rich in sugar and protein. As such, the T1Rs are low-affinity receptors mediating behavioral preference thresholds in the millimolar range (Damak et al., 2003Damak S. Rong M. Yasumatsu K. Kokrashvili Z. Varadarajan V. Zou S. Jiang P. Ninomiya Y. Margolskee R.F. Detection of sweet and umami taste in the absence of taste receptor T1r3.Science. 2003; 301: 850-853Crossref PubMed Scopus (451) Google Scholar, Zhao et al., 2003Zhao G.Q. Zhang Y. Hoon M.A. Chandrashekar J. Erlenbach I. Ryba N.J. Zuker C.S. The receptors for mammalian sweet and umami taste.Cell. 2003; 115: 255-266Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar); such low affinity helps the receptors distinguish between different potential sugar and protein sources without reaching saturation below nutritionally relevant concentrations. Bitter recognition faces a different challenge. Not only is the chemical diversity of bitter substances orders of magnitude greater, but in addition these toxic compounds must be detected at much smaller concentrations in order to avoid potentially lethal dietary mistakes. To accomplish this task, mammals are endowed with a family of GPCRs encoding the T2R bitter receptors (Adler et al., 2000Adler E. Hoon M.A. Mueller K.L. Chandrashekar J. Ryba N.J. Zuker C.S. A novel family of mammalian taste receptors.Cell. 2000; 100: 693-702Abstract Full Text Full Text PDF PubMed Scopus (990) Google Scholar, Chandrashekar et al., 2000Chandrashekar J. Mueller K.L. Hoon M.A. Adler E. Feng L. Guo W. Zuker C.S. Ryba N.J. T2Rs function as bitter taste receptors.Cell. 2000; 100: 703-711Abstract Full Text Full Text PDF PubMed Scopus (1028) Google Scholar, Matsunami et al., 2000Matsunami H. Montmayeur J.P. Buck L.B. A family of candidate taste receptors in human and mouse.Nature. 2000; 404: 601-604Crossref PubMed Scopus (549) Google Scholar). The T2Rs have a highly variable structure with few regions of extended conservation; this sequence diversity reflects the need to recognize a disparate chemical universe. T2Rs are both necessary and sufficient for bitter taste. On the one hand, knockout (Mueller et al., 2005Mueller K.L. Hoon M.A. Erlenbach I. Chandrashekar J. Zuker C.S. Ryba N.J. The receptors and coding logic for bitter taste.Nature. 2005; 434: 225-229Crossref PubMed Scopus (374) Google Scholar) or genetic alterations (Kim et al., 2003Kim U.K. Jorgenson E. Coon H. Leppert M. Risch N. Drayna D. Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide.Science. 2003; 299: 1221-1225Crossref PubMed Scopus (639) Google Scholar, Bufe et al., 2005Bufe B. Breslin P.A. Kuhn C. Reed D.R. Tharp C.D. Slack J.P. Kim U.K. Drayna D. Meyerhof W. The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception.Curr. Biol. 2005; 15: 322-327Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar) of specific T2Rs leads to changes in bitter taste sensitivity and selectivity. On the other, introduction of novel T2Rs expands the bitter taste repertoire (Mueller et al., 2005Mueller K.L. Hoon M.A. Erlenbach I. Chandrashekar J. Zuker C.S. Ryba N.J. The receptors and coding logic for bitter taste.Nature. 2005; 434: 225-229Crossref PubMed Scopus (374) Google Scholar). Ligands for several mouse and human T2Rs have been identified in cell-based assays, and as expected, all are bitter to humans or aversive to mice (Chandrashekar et al., 2000Chandrashekar J. Mueller K.L. Hoon M.A. Adler E. Feng L. Guo W. Zuker C.S. Ryba N.J. T2Rs function as bitter taste receptors.Cell. 2000; 100: 703-711Abstract Full Text Full Text PDF PubMed Scopus (1028) Google Scholar, Bufe et al., 2002Bufe B. Hofmann T. Krautwurst D. Raguse J.D. Meyerhof W. The human TAS2R16 receptor mediates bitter taste in response to beta-glucopyranosides.Nat. Genet. 2002; 32: 397-401Crossref PubMed Scopus (330) Google Scholar, Pronin et al., 2004Pronin A.N. Tang H. Connor J. Keung W. Identification of ligands for two human bitter T2R receptors.Chem. Senses. 2004; 29: 583-593Crossref PubMed Scopus (136) Google Scholar, Meyerhof et al., 2005Meyerhof W. Behrens M. Brockhoff A. Bufe B. Kuhn C. Human bitter taste perception.Chem. Senses. 2005; 30: i14-i15Crossref PubMed Scopus (37) Google Scholar). Given that there are far fewer T2Rs (ranging from about 10 to 40 members, depending on the species) than chemically distinct bitter-tasting chemicals, it is not surprising that any given T2R actually recognizes a wide repertoire of ligands (Meyerhof et al., 2005Meyerhof W. Behrens M. Brockhoff A. Bufe B. Kuhn C. Human bitter taste perception.Chem. Senses. 2005; 30: i14-i15Crossref PubMed Scopus (37) Google Scholar). Interestingly, some compounds, for example acesulfame K and saccharin, evoke sweetness at low concentrations but bitter responses at high concentrations. What underlies this duality of response? As it turns out, not only do these two artificial sweeteners activate the sweet taste receptor (Nelson et al., 2001Nelson G. Hoon M.A. Chandrashekar J. Zhang Y. Ryba N.J. Zuker C.S. Mammalian sweet taste receptors.Cell. 2001; 106: 381-390Abstract Full Text Full Text PDF PubMed Scopus (1299) Google Scholar, Li et al., 2002Li X. Staszewski L. Xu H. Durick K. Zoller M. Adler E. Human receptors for sweet and umami taste.Proc. Natl. Acad. Sci. USA. 2002; 99: 4692-4696Crossref PubMed Scopus (1049) Google Scholar), but in addition they also activate specific T2Rs at high concentration (Kuhn et al., 2004Kuhn C. Bufe B. Winnig M. Hofmann T. Frank O. Behrens M. Lewtschenko T. Slack J.P. Ward C.D. Meyerhof W. Bitter taste receptors for saccharin and acesulfame K.J. Neurosci. 2004; 24: 10260-10265Crossref PubMed Scopus (275) Google Scholar, Pronin et al., 2007Pronin A.N. Xu H. Tang H. Zhang L. Li Q. Li X. Specific alleles of bitter receptor genes influence human sensitivity to the bitterness of aloin and saccharin.Curr. Biol. 2007; 17: 1403-1408Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). This observation nicely illustrates the concept that a single chemical species may elicit more than one taste (i.e., through the activation of multiple receptors) and may explain the characteristic “aftertaste” associated with these tastants. Why do chemically diverse compounds generate a common sensation of bitterness? Studies of the expression of T2R transcripts in TRCs showed that each bitter-sensing cell coexpressess the majority of the T2R genes (Adler et al., 2000Adler E. Hoon M.A. Mueller K.L. Chandrashekar J. Ryba N.J. Zuker C.S. A novel family of mammalian taste receptors.Cell. 2000; 100: 693-702Abstract Full Text Full Text PDF PubMed Scopus (990) Google Scholar, Mueller et al., 2005Mueller K.L. Hoon M.A. Erlenbach I. Chandrashekar J. Zuker C.S. Ryba N.J. The receptors and coding logic for bitter taste.Nature. 2005; 434: 225-229Crossref PubMed Scopus (374) Google Scholar, Meyerhof et al., 2005Meyerhof W. Behrens M. Brockhoff A. Bufe B. Kuhn C. Human bitter taste perception.Chem. Senses. 2005; 30: i14-i15Crossref PubMed Scopus (37) Google Scholar). Given this lack of selectivity in the expression of T2Rs, Adler et al. proposed that bitter TRCs detect a wide range of toxic chemicals but do not discriminate between them. Indeed, subsequent behavioral studies demonstrated that rodents are unable to discriminate between bitter compounds (Spector and Kopka, 2002Spector A.C. Kopka S.L. Rats fail to discriminate quinine from denatonium: implications for the neural coding of bitter-tasting compounds.J. Neurosci. 2002; 22: 1937-1941PubMed Google Scholar), and molecular studies showed that taste-blind animals engineered to restore bitter taste function under the control of single T2R promoters recovered taste recognition to the entire repertoire of bitters (Zhang et al., 2003Zhang Y. Hoon M.A. Chandrashekar J. Mueller K.L. Cook B. Wu D. Zuker C.S. Ryba N.J. Coding of sweet, bitter, and umami tastes: Different receptor cells sharing similar signaling pathways.Cell. 2003; 112: 293-301Abstract Full Text Full Text PDF PubMed Scopus (945) Google Scholar, Mueller et al., 2005Mueller K.L. Hoon M.A. Erlenbach I. Chandrashekar J. Zuker C.S. Ryba N.J. The receptors and coding logic for bitter taste.Nature. 2005; 434: 225-229Crossref PubMed Scopus (374) Google Scholar). We suggest that this is exactly the type of sensor needed to warn against the ingestion of noxious substances and provides a nice biological underpinning to the observation that many human cultures use a single word to define bitter-tasting compounds. Sour-sensing TRCs are characterized by the expression of PKD2L1, a TRP ion channel proposed to function as a component of the acid-sensing machinery (LopezJimenez et al., 2006LopezJimenez N.D. Cavenagh M.M. Sainz E. Cruz-Ithier M.A. Battey J.F. Sullivan S.L. Two members of the TRPP family of ion channels, Pkd1l3 and Pkd2l1, are co-expressed in a subset of taste receptor cells.J. Neurochem. 2006; 98: 68-77Crossref PubMed Scopus (139) Google Scholar, Ishimaru et al., 2006Ishimaru Y. Inada H. Kubota M. Zhuang H. Tominaga M. Matsunami H. Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor.Proc. Natl. Acad. Sci. USA. 2006; 103: 12569-12574Crossref PubMed Scopus (357) Google Scholar, Huang et al., 2006Huang A.L. Chen X. Hoon M.A. Chandrashekar J. Guo W. Trankner D. Ryba N.J. Zuker C.S. The cells and logic for mammalian sour taste detection.Nature. 2006; 442: 934-938Crossref PubMed Scopus (552) Google Scholar). Genetic ablation of these cells via targeted expression of diphtheria toxin specifically and completely abolishes taste responses to acids, without affecting the other four taste qualities (Huang et al., 2006Huang A.L. Chen X. Hoon M.A. Chandrashekar J. Guo W. Trankner D. Ryba N.J. Zuker C.S. The cells and logic for mammalian sour taste detection.Nature. 2006; 442: 934-938Crossref PubMed Scopus (552) Google Scholar). How might PKD2L1-expressing TRCs sense acid? It has been argued that intracellular acidification is the relevant stimulus for sour taste (Lyall et al., 2001Lyall V. Alam R.I. Phan D.Q. Ereso G.L. Phan T.H. Malik S.A. Montrose M.H. Chu S. Heck G.L. Feldman G.M. et al.Decrease in rat taste receptor cell intracellular pH is the proximate stimulus in sour taste transduction.Am. J. Physiol. 2001; 281: C1005-C1013Google Scholar). However, recent experiments demonstrate that specific inhibition of extracellular proton production on the tongue is sufficient to block the activation of sour cells (Chandrashekar et al., 2009Chandrashekar J. Yarmolinsky D. von Buchholtz L. Oka Y. Sly W. Ryba N.J.P. Zuker C.S. The taste of carbonation.Science. 2009; 326: 455-458Crossref Scopus (242) Google Scholar), thus suggesting that the sour sensor operates instead as an extracellular receptor (see below). Several candidate receptors have been p
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