The first description of taste-related signaling components in the airway was a report by Zancanaro and colleagues describing the presence of gustducin-expressing cells in the vomeronasal organ [29
], which is a specialized part of the olfactory system found in many vertebrates but absent in adult humans. The gustducin-expressing cells in the vomeronasal organ are scattered epithelial cells mainly distributed along the incoming ducts of the organ and within the non-sensory epithelium of the organ itself. The morphology of these cells is similar to chemosensory cells scattered within the epidermis of fishes as first described by Mary Whitear in the 1960s [30
] when she referred to them as solitary chemosensory cells (SCCs).
Subsequently, we and others showed that SCCs are present throughout the upper respiratory system and express the entire suite of taste-related signaling molecules, including T2R receptors, PLCβ2, gustducin, and the transduction channel TrpM5 [9
]. Finger et al. [9
] demonstrated that the taste signaling cascade is necessary for activation of the SCCs. Since the SCCs synapse onto polymodal pain fibers of the trigeminal nerve, activation of the SCCs by bitter ligands evokes trigeminally-mediated reflex changes in respiration. So inhalation of a toxin that activates T2R receptors will be irritating and will provoke reflex changes in respiration [11
]—not a sensation of taste. More recently, we showed that even some bacterial metabolites and signal molecules can activate the nasal SCCs and trigeminal nerve [11
]. Since the activated trigeminal nerve fibers release peptide modulators (e.g., substance P or calcitonin gene-related peptide), this causes local neurogenic inflammation of the respiratory epithelium. In this way, SCCs act not only as sentinels warning against inhalation of irritants, but also as guardians capable of activating the innate immune system to the presence of potentially damaging toxins or pathogens.
In all of the examples presented so far, the taste signaling cascade is used to detect elements in the lumen of an organ (tongue, gut, respiratory passages), and to generate an intracellular cascade to effect release of a neurotransmitter or hormone to signal to other cells in the body. Two recent reports on the expression of “taste” receptors in the airways indicate that taste receptor signaling may also operate in a cell-autonomous fashion, that is, detection of the chemical directly affects function of the responsive cell.
The first such report of a cell-autonomous effect of T2R activation was in ciliated cells of human lower airways [32
]. Cultured human airway epithelium expresses some T2Rs along with associated downstream elements. Curiously though, the T2Rs are present on the cilia of the ciliated epithelial cells with PLCβ2 situated where the cilia insert into the cell body. In this scenario, the T2R-mediated increase in intracellular Ca2+
causes an increase in ciliary beat frequency (), which the authors suggest would serve to sweep irritants away from the surface of the cell. Whereas T2Rs can be detected in cultured human airway cells, they are not detected in the lower airways of mice [33
]. Whether this represents a species difference or the difference between in vivo
(mouse) and in vitro
(human) states remains to be determined.
The second report of T2Rs directing function within an airway cell came from Deshpande and colleagues [34
] showing that smooth muscle cells of human airways express T2R (bitter) taste receptors along with gustducin and some components of the taste-associated PLC signaling cascade. Application of various bitter-tasting substances to cultured human airway smooth muscle cells produces PLC-dependent increases in intracellular Ca2+
as would be typical of taste cells or SCCs. Surprisingly, these increases in intracellular Ca2+
are reported to cause relaxation rather than contraction of muscle, which is what is normally seen with increases in intracellular Ca2+
. This apparently paradoxical effect in the airway smooth muscle cells is attributed to the proximity of the T2R receptor complex to calcium-activated big potassium (BKCa
) channels (), which open in response to increased intracellular Ca2+
. Opening of the BKCa
channels directly hyperpolarizes the muscle cell leading to relaxation. In contrast, in taste cells and SCCs, activation of the T2R receptor causes increased intracellular Ca2+
, as in the airway smooth muscle, but in the sensory cells, the increased intracellular Ca2+
triggers the transduction channel TrpM5 to depolarize the cell and evoke transmitter release. Thus in different signaling contexts, activation of the same receptor can produce opposite cellular-level effects. It should be noted, however, that the findings of Deshpande and colleagues [34
] have since been questioned in terms of specificity and mechanism; see [35