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Biased TAS2R Bronchodilators Inhibit Airway Smooth Muscle Growth by Downregulating pERK1/2

Kim, Donghwan and Cho, Soomin and Castaño, Maria A. and Panettieri, Reynold A. and Woo, Jung A. and Liggett, Stephen B. (2019) Biased TAS2R Bronchodilators Inhibit Airway Smooth Muscle Growth by Downregulating pERK1/2. American Journal of Respiratory Cell and Molecular Biology, 60 (5). pp. 532-540. ISSN 1044-1549. doi:10.1165/rcmb.2018-0189OC.

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Bitter taste receptor (TAS2R) agonists dilate airways by receptor-dependent smooth muscle relaxation. Besides coupling to relaxation, we have found that human airway smooth muscle (HASM) cell TAS2Rs activate (phosphorylate) ERK1/2, but the cellular effects are not known. Here we show in HASM cells that TAS2R agonists initially stimulate pERK1/2, but by 24 hrs cause a marked (50-70%) downregulation of pERK1/2 without a change in total ERK1/2. It was hypothesized that TAS2R agonists suppress cell growth through this pERK1/2 downregulation. Agonist-dependent inhibition of cell proliferation was indeed found in HASM cells derived from normal and asthmatic human lungs, as well as an immortalized HASM cell line. pERK1/2 downregulation was linked to downregulation of the upstream kinase MEK1/2. Various structurally diverse TAS2R agonists evoked a range of inhibition of HASM proliferation, the magnitude of which directly correlated with the downregulation of pERK1/2 (R2 = 0.86). Some TAS2R agonists were as effective in suppressing growth as pharmacological inhibitors of Raf1 and MEK1/2. siRNA silencing of TAS2Rs (subtypes 10, 14, 31) ablated the pERK1/2 and growth inhibiting effects of TAS2R agonists. These phenotypes were attenuated by inhibiting the TAS2R G-protein Gα, and by knocking-down β-arrestin1/2, indicating a dual pathway, although there may be additional mechanisms involved in this HASM TAS2R multidimensional signaling. Thus TAS2R agonist structure can be manipulated to maintain the relaxation response, and be biased towards suppression of HASM growth. The latter response is of potential therapeutic benefit in asthma, where an increase in smooth muscle mass contributes to airway obstruction.

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Additional Information:© 2018 American Thoracic Society. Supported by National Institutes of Health grants HL045967 (S.B.L.) and HL114471 (S.B.L. and R.A.P.). Author Contributions: Conception, design, and conduct of experiments; analysis of data; and interpretation of results: D.K., S.C., M.A.C., J.A.W., and S.B.L.; and writing and preparation of the manuscript: D.K., R.A.P., J.A.W., and S.B.L.
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Subject Keywords:Asthma, G-protein, MAP kinase, bitter taste receptor
Issue or Number:5
Record Number:CaltechAUTHORS:20181105-083012568
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90626
Deposited By: Tony Diaz
Deposited On:06 Nov 2018 18:25
Last Modified:16 Nov 2021 03:34

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