TAS2R activation promotes airway smooth muscle relaxation despite β(2)-adrenergic receptor tachyphylaxis.
ABSTRACT Recently, bitter taste receptors (TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca(2+) concentration signaling generated from restricted phospholipase C activation. As potential therapy, TAS2R agonists could be add-on treatment when patients fail to achieve adequate bronchodilation with chronic β-agonists. The β(2)-adrenergic receptor (β(2)AR) of ASM undergoes extensive functional desensitization. It remains unknown whether this desensitization affects TAS2R function, by cross talk at the receptors or distal common components in the relaxation machinery. We studied intracellular signaling and cell mechanics using isolated human ASM, mouse tracheal responses, and human bronchial responses to characterize TAS2R relaxation in the context of β(2)AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed >90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of β(2)AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca(2+) concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by >90%. In mouse trachea, β(2)AR desensitization by β-agonist amounted to 92 ± 6.0% (P < 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 ± 3.5%). In human lung slices, chronic β-agonist exposure culminated in 64 ± 5.7% (P < 0.001) desensitization of β(2)AR-mediated dilation of carbachol-constricted airways that was reversed by chloroquine. We conclude that there is no evidence for physiologically relevant cross-desensitization of TAS2R-mediated ASM relaxation from chronic β-agonist treatment. These findings portend a favorable therapeutic profile for TAS2R agonists for the treatment of bronchospasm in asthma or chronic obstructive lung disease.
Article: Taste receptors in innate immunity[Show abstract] [Hide abstract]
ABSTRACT: Taste receptors were first identified on the tongue, where they initiate a signaling pathway that communicates information to the brain about the nutrient content or potential toxicity of ingested foods. However, recent research has shown that taste receptors are also expressed in a myriad of other tissues, from the airway and gastrointestinal epithelia to the pancreas and brain. The functions of many of these extraoral taste receptors remain unknown, but emerging evidence suggests that bitter and sweet taste receptors in the airway are important sentinels of innate immunity. This review discusses taste receptor signaling, focusing on the G-protein-coupled receptors that detect bitter, sweet, and savory tastes, followed by an overview of extraoral taste receptors and in-depth discussion of studies demonstrating the roles of taste receptors in airway innate immunity. Future research on extraoral taste receptors has significant potential for identification of novel immune mechanisms and insights into host-pathogen interactions.Cellular and Molecular Life Sciences CMLS 10/2014; 72(2). DOI:10.1007/s00018-014-1736-7 · 5.86 Impact Factor
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ABSTRACT: There is a need to expand the classes of drugs used to treat obstructive lung diseases to achieve better outcomes. With only one class of direct bronchodilators (β-agonists), we sought to find receptors on human airway smooth muscle (ASM) that act via a unique mechanism to relax the muscle, have a diverse agonist binding profile to enhance the probability of finding new therapeutics, and relax ASM with equal or greater efficacy than β-agonists. We have found that human and mouse ASM express six bitter taste receptor (TAS2R) subtypes, previously thought only to exist in taste buds of the tongue. Agonists acting at TAS2Rs evoke profound bronchodilation via a Ca(2+)-dependent mechanism. TAS2R function is not altered in asthma models, undergoes minimal tachyphylaxis upon repetitive dosing, and relaxes even under extreme desensitization of relaxation by β-agonists. Taken together, TAS2Rs on ASM represent a novel pathway to consider for development of agonists in the treatment of asthma and chronic obstructive lung disease.Transactions of the American Clinical and Climatological Association 01/2014; 125:64-75.
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ABSTRACT: Taste receptors on the tongue communicate information to the brain about the nutrient content or potential toxicity of ingested foods. However, recent research has now shown that taste receptors are also expressed far beyond the tongue, from the airway and gastrointestinal epithelia to the pancreas and brain. The functions of many of these so-called extraoral taste receptors remain unknown, but emerging basic science and clinical evidence suggests that bitter and sweet taste receptors in the airway are important in sensing bacteria and regulating innate immunity. This review focuses on the role of bitter and sweet taste receptors in human airway innate immunity and the potential clinical relevance to airway infections. The T2R38 bitter taste receptor in sinonasal cilia detects bitter bacterial quorum-sensing molecules and activates nitric oxide-dependent innate immune responses. Polymorphisms that underlie T2R38 functionality also appear to be involved in susceptibility to upper respiratory infection and chronic rhinosinusitis (CRS). Bitter and sweet receptors in specialized sinonasal solitary chemosensory cells control antimicrobial peptide secretion, which may have important implications for airway infections in CRS patients as well as patients with diabetes mellitus. Future research on taste receptors in the airway has tremendous potential to identify immune mechanisms involved in host-pathogen interactions and thus reveal novel therapeutic targets.Journal of Molecular Medicine 11/2014; DOI:10.1007/s00109-014-1222-6 · 4.74 Impact Factor