A CREB‐mediated increase in miRNAlet‐7fduring prolonged β‐agonist exposure: a novel mechanism of β2‐adrenergic receptor down‐regulation in airway smooth muscle

What is it about?

In asthma, airway smooth muscle contracts, leading to airflow obstruction. β-agonist treatment targets the β2-adrenergic receptor on airway smooth muscle which causes relaxation. During prolonged β-agonist treatment, β2-adrenergic receptors on the smooth muscle display reduced capacity to relax. This downregulation limits the effectiveness of β-agonist treatment, which is a particular problem in moderate and severe asthma. In this paper, we have determined a main mechanism of the downregulation process. Intracellular cAMP, the product of receptor activation, causes phosphorylation of a transcription factor (CREB) which increases expression of a microRNA termed let-7f. let-7f then binds to the 3' untranslated region of the β2-adrenergic gene and represses its translation to mature receptor protein. Knowing this pathway will provide for a means to limit downregulation and thus significantly improve asthma therapy with β-agonists.

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