Department of Surgery; Department of Microbiology and Physiological Systems; Program in Molecular Medicine; Biomedical Imaging Group
Amino Acids, Peptides, and Proteins | Animal Experimentation and Research | Cells | Cellular and Molecular Physiology | Chemical Actions and Uses | Chemicals and Drugs | Investigative Techniques | Molecular Biology | Pharmaceutical Preparations | Respiratory System | Respiratory Tract Diseases | Therapeutics
Bronchodilators are a standard medicine for treating airway obstructive diseases, and beta2 adrenergic receptor agonists have been the most commonly used bronchodilators since their discovery. Strikingly, activation of G-protein-coupled bitter taste receptors (TAS2Rs) in airway smooth muscle (ASM) causes a stronger bronchodilation in vitro and in vivo than beta2 agonists, implying that new and better bronchodilators could be developed. A critical step towards realizing this potential is to understand the mechanisms underlying this bronchodilation, which remain ill-defined. An influential hypothesis argues that bitter tastants generate localized Ca(2+) signals, as revealed in cultured ASM cells, to activate large-conductance Ca(2+)-activated K(+) channels, which in turn hyperpolarize the membrane, leading to relaxation. Here we report that in mouse primary ASM cells bitter tastants neither evoke localized Ca(2+) events nor alter spontaneous local Ca(2+) transients. Interestingly, they increase global intracellular [Ca(2+)]i, although to a much lower level than bronchoconstrictors. We show that these Ca(2+) changes in cells at rest are mediated via activation of the canonical bitter taste signaling cascade (i.e., TAS2R-gustducin-phospholipase Cbeta [PLCbeta]- inositol 1,4,5-triphosphate receptor [IP3R]), and are not sufficient to impact airway contractility. But activation of TAS2Rs fully reverses the increase in [Ca(2+)]i induced by bronchoconstrictors, and this lowering of the [Ca(2+)]i is necessary for bitter tastant-induced ASM cell relaxation. We further show that bitter tastants inhibit L-type voltage-dependent Ca(2+) channels (VDCCs), resulting in reversal in [Ca(2+)]i, and this inhibition can be prevented by pertussis toxin and G-protein betagamma subunit inhibitors, but not by the blockers of PLCbeta and IP3R. Together, we suggest that TAS2R stimulation activates two opposing Ca(2+) signaling pathways via Gbetagamma to increase [Ca(2+)]i at rest while blocking activated L-type VDCCs to induce bronchodilation of contracted ASM. We propose that the large decrease in [Ca(2+)]i caused by effective tastant bronchodilators provides an efficient cell-based screening method for identifying potent dilators from among the many thousands of available bitter tastants.
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Copyright: 2013 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
PLoS Biol. 2013;11(3):e1001501. doi: 10.1371/journal.pbio.1001501. Link to article on publisher's site
PLoS biology doi:10.1371/annotation/7899a865-d68b-45bd-8b9b-ec6f50c9308a
Zhang C, Lifshitz LM, Uy K, Ikebe M, Fogarty KE, ZhuGe R. (2013). The cellular and molecular basis of bitter tastant-induced bronchodilation. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1371/journal.pbio.1001501. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/247
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