…there are taste buds in the respiratory tract?
There are taste receptors in the airways, and moreover that they may be future targets for treating obstructive airway diseases? Most are familiar with epithelial sensory receptors, first identified in 2000, on the tongue and palate as they allow us to differentiate bitter tastants . However, bitter taste receptors, or TAS2Rs, are also surprisingly located in several extraoral locations, including pulmonary and vascular tissues. For example, in 2003, TAS2Rs were discovered in the nasal cavity where they regulate respiratory rate and promote sneezing . In addition, in 2009, TAS2Rs on ciliated epithelial cells in the nasal cavity were shown to increase beat frequency . Perhaps most intriguing, airway smooth muscle (ASM) expression of TAS2Rs was observed to regulate bronchial tone .
Signaling cascades of TAS2Rs and GPCRs in ASM cells to regulate bronchodilation and bronchoconstriction. Adapted from [3, 9].Figure 1A. GPCR signaling leading to ASM relaxation and bronchodilation. In ASM, activation of TAS2Rs and Ggust in localized regions of the cell may lead to increased intracellular calcium, activation of membrane channels including large conductance calcium dependent potassium channels (BKCa) leading to membrane hyperpolarization, and potent ASM relaxation (black lines). Also, activated TAS2Rs may directly inhibit L-type voltage dependent calcium channels (VDCC) and blunt agonist induced calcium influx, leading to ASM relaxation (red lines). Activation of β2-Adrenergic receptors elicit airway smooth relaxation by Gs coupled activation of adenylate cyclase (AC), production of cyclic AMP (cAMP) and activation of protein kinase A (PKA), which phosphorylates multiple substrates to decrease intracellular cell calcium concentration. Decreasing calcium reduces activation of myosin light chain kinase (MLCK) thus favoring myosin light chain dephosphorylation by myosin phosphatase (complex of PP1c, MYPT and M20) and relaxation of ASM. Figure 1B. GPCR signaling leading to ASM contraction and bronchoconstriction. Bronchoconstrictor agonists activate multiple GPCRs and elicit ASM contraction through activation of multiple downstream signaling pathways that ultimately increase intracellular calcium. Intracellular calcium interacts with calmodulin to activate myosin light chain kinase (MLCK). Increasing calcium increases activation of MLCK thus favoring myosin light chain phosphorylation and contraction of ASM.
TAS2Rs are G protein-coupled receptors (GPCRs). A variety of other GPCRs on ASM regulate bronchial tone and serve as therapeutic targets for obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) . These standard-of-care therapies (β-agonists) signal through the β2 adrenergic receptor, a GPCR, and increase the second messenger cAMP leading to relaxation of ASM and bronchodilation (Figure 1A). In contrast, contractile agonists such as leukotriene-D4, acetylcholine and histamine signal through other GPCRs and increase intracellular calcium leading to contraction of ASM and bronchoconstriction (Figure 1B).
On oral sensory epithelia, bitter compounds activate TAS2Rs and lead to increased intracellular calcium, TRP channel activation, membrane depolarization, and neurotransmitter release. Since increased intracellular calcium and membrane depolarization on ASM promote bronchoconstriction, the discovery of TAS2Rs on ASM led to the hypothesis that TAS2Rs would mediate increased intracellular calcium on ASM and subsequent bronchoconstriction. However, a series of experiments by Stephen Liggett and colleagues revealed that agonist-induced activation of bitter taste receptors on ASM cells caused localized calcium-dependent signaling leading to membrane hyperpolarization, and marked airway smooth muscle relaxation (Figure 1A) . These results are now under debate as data from other groups shows activation of TAS2Rs does not produce a localized calcium increase. The suggested alternative is that TAS2R activation prevents agonist-induced contraction by limiting calcium influx through L-type voltage dependent calcium channels, thereby reducing calcium sensitivity leading to ASM relaxation (Figure 1A) [6, 7].
Regardless of the specific mechanism, delivery of bitter tastants proved more effective at reversing acute airway bronchoconstriction than β-agonists in experimental asthma [3, 8]. Thus, if issues regarding selectivity, toxicity, distribution, and palatability of bitter tastants can be solved, future drug therapy to control obstructive airway diseases may leave more than a bitter taste behind .
Author: Jared M. McLendon, October 2014
Chief Editor: Robert Barrington, Ph.D.
Co-Editor: Adam Morrow, Ph.D.
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