2. Receptor molecules

Molecular studies have identified two families of G-protein-coupled receptors, which are expressed in distinct cell types. Two receptors of one family are thought to mediate two basic tastes: sweet and umami. A second family of several receptors is thought to mediate the bitter tastes. The functional roles of these molecules have been examined by expression profiles, imaging of calcium responses to tastants by cultured cells containing the molecules, and studies of behavioral and neurophysiological responses to tastants in animals who did not have the intact molecules, such as naturally occurring mutants and genetically created “knock-out” mice. Labeled lines were inferred (reviewed in Chandrashekar et al. Reference Chandrashekar, Hoon, Ryba and Zucker2006). It is disappointing that the stimuli used to show the presence or lack of responses were only compounds known to elicit, or potentiate the presumed basic tastes – sweet, salty, sour, bitter, and umami (e.g., see Li et al. Reference Li, Staszewski, Xu, Durick, Zoller and Adler2002; Zhang et al. Reference Zhang, Hoon, Chandrashekar, Mueller, Cook, Wu, Zuker and Ryba2003). Thus, these studies assumed the hypothesis of basic tastes and collected data to support it and the labeled-line hypothesis, but did not test the hypotheses. It remains possible that the molecules could respond to other tastants.

The putative sweet receptor is a heterodimer (T1R2/T1R3), which contains multiple sites for binding sweet compounds consisting of a variety of structures. These include pockets in the N-termini of both subunits for sugars, D-amino acids, and various “artificial” sweeteners, a cysteine-rich area in the T1R3 subunit for the protein brazzein, and the transmembrane region of T1R3 for Na-cyclamate, the sweet inhibitor lactisole, and perhaps also Na-saccharin and acesulfame-K (Galindo-Cuspinera et al. Reference Galindo-Cuspinera, Winning, Bufe, Meyerhof and Breslin2006; Jiang et al. Reference Jiang, Ji, Liu, Snyder, Benard, Margolskee and Max2004; Reference Jiang, Cui, Snyder, Benard, Osman, Max and Margolskee2005; Morini et al. Reference Morini, Bassoli and Temussi2005; Xu et al. Reference Xu, Staszewski, Tang, Adler, Zoller and Li2004). Although not discussed in the literature, this complex molecule could bind various other stimuli, as well. The putative umami and bitter receptors also could bind other stimuli. One could propose the alternative hypothesis, that is, the receptor molecules are broadly tuned so as to participate in across-fiber patterning and thus would bind a variety of taste stimuli, perhaps responding “best” to one or another tastant. Then, a variety of tastants, including those known to elicit the basic tastes, other “singular” tasting compounds (as in Erickson), and those known to elicit complex tastes, could be tested. The results could allow the researchers to disprove one coding hypothesis and support the other.

3. Receptor cells

As noted by Erickson, a large body of data shows that taste neurons respond to more than one type of taste stimulus. In particular, rodent and frog data from many laboratories show that taste bud cells respond to more than one type of taste stimulus (reviewed in Herness Reference Herness2000). Yet, a given receptor cell expresses only one type of receptor molecule (Chandrashekar et al. Reference Chandrashekar, Hoon, Ryba and Zucker2006). If the molecules are narrowly tuned for a basic taste quality, then the cells should be narrowly tuned, as well. Recent work combined calcium imaging in mouse lingual slices and molecular techniques to address this paradox. Two types of taste bud cells – “receptor cells” and “presynaptic cells” – were found. Most receptor cells responded to only one of stimuli for sweet, umami, or bitter tastes, whereas the presynaptic cells responded to stimuli for all the basic tastes, including sour and salty. It was proposed that presynaptic cells receive inputs from receptor cells via ATP and that both the receptor and presynaptic cells transmit information to afferent fibers (DeFazio et al. Reference DeFazio, Dvoryanichikov, Maruyama, Kim, Pereira, Roper and Chaudhari2006; Tomchick et al. Reference Tomchik, Berg, Kim, Chaudhari and Roper2007). Again, only stimuli known to elicit the basic tastes were used. Moreover, as specific responses occurred in only 82% of the receptor cells, it seems possible that if more broadly tested, receptor cells might show broader response profiles. One would like to see the receptor cells tested with a variety of tastants, as suggested for the receptor molecules.

4. Coding mechanisms

Sugita (Reference Sugita2006) suggests that sweet and umami modalities mediate attraction, while bitter mediates aversion, and salty and sour mediate attraction or aversion, depending on the concentrations. Indeed, expression of a receptor that binds spiradoline, a tasteless compound, in mouse bitter- or sweet-receptor expressing cells led to behavioral rejection of spiradoline in the former case, and attraction in the latter case (Zhao et al. Reference Zhao, Zhang, Hoon, Chandrashekar, Erlenbach, Ryba and Zuker2003). In the mid-20th century, fly taste receptor cells initially were thought to code for two modalities – “acceptance” and “rejection.” Fly researchers limited their choice of stimuli to the four basic tastes, and the “sugar,” “salt,” “water,” and “fifth” receptor cells became viewed as labeled lines. Data indicate that the sugar and water cells mediate behavioral attraction, the fifth cell mediates rejection, and the salt cell mediates attraction or rejection depending on the concentration (reviewed in Dethier Reference Dethier1976). Dethier (Reference Dethier1974) questioned whether the “rigid specificity” of these labeled lines “existed more in the minds of investigators than in the receptors themselves.” He showed that the cells responded to a variety of unusual compounds and natural foods with spectra of activity that were unique, with little or no overlap. Dethier proposed that the taste sensory message in flies is two-fold: first, there is coding for acceptance or rejection, and second, across-fiber patterning might provide the “potential for discrimination among many substances.” Perhaps labeled lines and across-fiber patterning provide similar separate messages in vertebrates.