PerspectiveCell Biology

Using Taste to Clear the Air(ways)

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Science  28 Aug 2009:
Vol. 325, Issue 5944, pp. 1081-1082
DOI: 10.1126/science.1179180

Epithelial cells that line the human airway are constantly bombarded by environmental hazards, including toxins, irritants, viruses, and bacteria. The airway rids itself of these agents by secreting mucus to “capture” harmful substances and increasing the beat frequency of motile cilia on epithelial cells to sweep the mucus out of the system. Protective reflexes such as coughing are also initiated. The mechanisms used to detect and respond to harmful agents are poorly understood. On page 1131 of this issue, Shah et al. (1) report that cultured human airway epithelial cells use elements of the bitter taste cellular signaling pathway to detect and eliminate potential noxious agents from the airways.

Surprisingly, Shah et al. find that several signaling molecules that respond to bitter compounds are expressed by ciliated airway epithelial cells, including the T2R family of bitter taste receptors, the heterotrimeric GTP-binding protein (G protein) α-gustducin, and the enzyme phospholipase C–β2 (PLC-β2). T2R receptors and G proteins are located in discrete zones on the ciliary shaft, whereas PLC-β2 is located just beneath the cilia in the apical portion of the cell. When stimulated with bitter compounds, the ciliated cells respond with an increase in intracellular calcium ion (Ca2+) concentration and a concomitant increase in ciliary beat frequency, which in vivo would presumably aid in removing noxious substances from the airways.

The study by Shah et al. is the first report of sensory function in motile cilia. It has been assumed that sensory receptors are only expressed on primary cilia, and that motile cilia have a purely motor function (2). However, in the green alga Chlamydomonas reinhardtii, ∼25% of the proteins found in flagella—the tail-like projection used for locomotion—function in signaling, suggesting a role for motile cilia in detecting light, oxygen, redox state, and small ligands (3). T2R receptors were not detected in a recent proteomic screen of human airway cilia (4), however. This difference may be due to specialization of ciliated cells in subregions of the airway. Shah et al. used proximal airway epithelial cells, which respond to certain agonists by increasing their ciliary beat frequency (5, 6). By contrast, cilia on distal airway cells beat at maximal frequency and are refractory to agonists that increase intracellular Ca2+ concentration (7, 8). Thus, use of this in vitro culture system may have facilitated identification of a molecularly distinct ciliated cell subset.

Bitter responses.

A similar signaling pathway is initiated by bitter compounds in taste cells and solitary chemosensory cells. Activated T2R receptors trigger the production of inositol 1,4,5-trisphosphate (IP3) and release of Ca2+ from internal stores. Ca2+ activates a nonselective cation channel, TrpM5, which depolarizes the cell and together with Ca2+ evokes the release of a transmitter that activates a target sensory neuron. In ciliated epithelial cells, bitter tastants signal through a similar pathway, but the functional outcome is an increased rate of ciliary beating.


Shah et al. demonstrate specific expression of T2R on cilia of cultured airway epithelial cells. However, immunohistochemical analysis detected other components of the T2R signaling pathway (α-gustducin and PLC-β2) in secretory cells of human and rat airway tissue (9) and on human pulmonary neuroendocrine cells (10). These observations raise several points that will provide a focus for future studies. First, if T2R receptors are present in human airway cells in vivo, are they restricted to ciliated cells of the bronchial surface epithelium and/or gland ducts? Second, the secretory cells that are presumably present in cultured bronchial airway cells may lack α-gustducin and PLC-β2. Is this a consequence of cellular origin or in vitro differentiation? Also, is mucus secretion by secretory cells coupled to the increase in intracellular Ca2+ concentration that ciliated epithelial cells exhibit in response to bitter substances? If so, this coordination would facilitate clearing the airways of noxious agents.

Why should airway epithelial cells express bitter “taste” receptors? There are about 25 members of the T2R receptor family in humans, each responsive to a broad array of bitter compounds when expressed in heterologous cells (11). Bitter receptors respond to potential toxic substances in foods. But T2R receptors are present in tissues other than taste buds. In the gut, these receptors are expressed in some enteroendocrine cells. When stimulated, they release hormones that modulate gut motility or evoke reflexes controlled by the vagus nerve (12). T2R receptors are also expressed in solitary chemoreceptor cells of the nasal epithelium (13). These cells respond to a variety of irritants, including stimuli that would taste bitter. Activation of these cells evokes protective airway reflexes such as sneezing, coughing, or apnea (14). In all cases studied to date, activation of T2R receptors activates a similar cell signaling pathway that results in a protective reflex to rid the body of the noxious agent (see the figure). In an innervated cell, the increase in intracellular Ca2+ concentration activates a nonselective cation channel, TrpM5, which depolarizes the cell and evokes the release of transmitters that activate target sensory nerves. In ciliated epithelial cells, the increase in intracellular Ca2+ concentration evokes an increase in ciliary beat frequency. The molecular details of the latter response now need to be fleshed out.

What is the natural ligand for T2R-expressing cells in the airways? Whereas taste cells and enteroendocrine cells are likely to encounter ingested bitter toxins, most bitter compounds are not volatile, but could be encountered as fine particulates. Shah et al. suggest that airway epithelial cells may respond to products secreted by pathogenic bacteria. This may also be a natural stimulus for solitary chemoreceptor cells in the airways (15, 16). T2R receptors in vitro respond to lactones (17), which are chemically similar to quorum signaling molecules secreted by Gram-negative bacteria. It will be interesting to determine if the proximal airway cells respond to these compounds.


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