A CREB-mediated Increase in MiRNA Let-7f during Prolonged Β-agonist Exposure: a Novel Mechanism of Β2-adrenergic Receptor Down-regulation in Airway Smooth Muscle

Authors

Donghwa Kim, University of South FloridaFollow
Soomin Cho, University of South Florida
Jung A. Woo, University of South FloridaFollow
Stephen B. Liggett, University of South FloridaFollow

Document Type

Article

Publication Date

2018

Keywords

G protein, tachyphylaxis, asthma, microRNA

Digital Object Identifier (DOI)

https://doi.org/10.1096/fj.201701278R

Abstract

β₂-Adrenergic receptors (β₂ARs) desensitize during continuous agonist activation, which manifests clinically as tachyphylaxis. β-Agonist desensitization of β₂ARs in human airway smooth muscle (HASM) cells is recognized in the treatment of asthma and maybe related to poor outcomes. Rapid events in desensitization include receptor phosphorylation and internalization, but mechanisms responsible for the decrease in receptor protein after prolonged agonist exposure (down-regulation) are ill defined. The microRNA (miRNA) let-7f regulates β₂AR expression by translational repression. In cultured HASM cells from nonasthmatic and asthmatic lungs, 18 h of β-agonist exposure increased let-7f by 2–3-fold, concomitant with a ~90% decrease in β₂ARs. Inhibition of let-7f attenuated this down-regulation response by ~50%. The let-7f increase was found to be cAMP/PKA-dependent. The mechanism of the let-7f increase was found by chromatin immunoprecipitation to be from activated cAMP response element-binding protein (CREB) binding to the let-7f promoter, thereby increasing let-7f expression. Knockdown of CREB attenuated agonist-promoted β₂AR down-regulation by ~50%. Thus, β₂AR down-regulation occurs as a result of not only internalized receptor degradation but also a novel cAMP/PKA/CREB-mediated increase in let-7f which causes enhanced repression of the β₂AR gene, adrenoreceptor β₂ (ADRB2) translation and represents ~50°% of the net loss of receptors observed after prolonged agonist exposure. This mechanism is apparent in asthmatic HASM cells, indicating relevance in a disease model.—Kim, D., Cho, S., Woo, J. A., Liggett, S.B. A CREB-mediated increase in miRNA let-7f during prolonged β-agonist exposure: a novel mechanism of β₂-adrenergic receptor down-regulation in airway smooth muscle. FASEB J. 32, 3680–3688 (2018). www.fasebj.org

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

The FASEB Journal, v. 32, issue 7, p. 3680-3688

Scholar Commons Citation

Kim, Donghwa; Cho, Soomin; Woo, Jung A.; and Liggett, Stephen B., "A CREB-mediated Increase in MiRNA Let-7f during Prolonged Β-agonist Exposure: a Novel Mechanism of Β2-adrenergic Receptor Down-regulation in Airway Smooth Muscle" (2018). Internal Medicine Faculty Publications. 233.
https://digitalcommons.usf.edu/intmed_facpub/233