Biased TAS2R Bronchodilators Inhibit Airway Smooth Muscle Growth by Downregulating Phosphorylated Extracellular Signal–regulated Kinase 1/2
Abstract
Bitter taste receptor (TAS2R) agonists dilate airways by receptor-dependent smooth muscle relaxation. Besides their coupling to relaxation, we have found that human airway smooth muscle (HASM) cell TAS2Rs activate (phosphorylate) extracellular signal–related kinase 1/2 (ERK1/2), but the cellular effects are not known. In the present study, we show in HASM cells that TAS2R agonists initially stimulate phosphorylated ERK1/2 (pERK1/2) but by 24 hours 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 in an immortalized HASM cell line. pERK1/2 downregulation was linked to downregulation of the upstream kinase MEK1/2 (mitogen-activated protein kinase/extracellular signal–regulated kinase). 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 (R^2 = 0.86). Some TAS2R agonists were as effective as pharmacological inhibitors of Raf1 and MEK1/2 in suppressing growth. siRNA silencing of TAS2Rs (subtypes 10, 14, and 31) ablated the pERK1/2 and growth-inhibitory effects of TAS2R agonists. These phenotypes were attenuated by inhibiting the TAS2R G protein G_(αi) and by knocking down β-arrestin 1/2, 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 can be biased toward suppression of HASM growth. The latter response is of potential therapeutic benefit in asthma, in which an increase in smooth muscle mass contributes to airway obstruction.
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.Attached Files
Supplemental Material - kim_data_supplement.pdf
Files
Name | Size | Download all |
---|---|---|
md5:5094edc4bf43472fce66a4c5cfd3a0c0
|
291.5 kB | Preview Download |
Additional details
- Eprint ID
- 95770
- DOI
- 10.1165/rcmb.2018-0189oc
- Resolver ID
- CaltechAUTHORS:20190523-153440847
- NIH
- HL045967
- NIH
- HL114471
- Created
-
2019-05-23Created from EPrint's datestamp field
- Updated
-
2021-11-16Created from EPrint's last_modified field