Epinephrine evokes shortening of human airway smooth muscle cells following β₂adrenergic receptor desensitization

Abstract

Epinephrine (EPI), an endogenous catecholamine involved in the body's fight-or-flight responses to stress, activates α1-adrenergic receptors (α1ARs) expressed on various organs to evoke a wide range of physiologic functions, including vasoconstriction. In the smooth muscle of human bronchi, however, the functional role of EPI on α1ARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating β2-adrenergic receptors (β2ARs). Conventionally, the selective β2AR agonism of EPI was thought to be, in part, due to a predominance of β2ARs and/or a sparse, or lack of α1AR activity in human airway smooth muscle (HASM) cells. Surprisingly, we find that HASM cells express a high abundance of ADRA1B (the α1AR subtype B) and identify a spontaneous 'switch-like' activation of α1ARs that evokes intracellular calcium, myosin light chain phosphorylation, and HASM cell shortening. The switch-like responses, and related EPI-induced biochemical and mechanical signals, emerged upon pharmacological inhibition of β2ARs and/or under experimental conditions that induce β2AR tachyphylaxis. EPI-induced pro-contractile effects were abrogated by an α1AR antagonist, doxazosin mesylate (DM). These data collectively uncover a previously unrecognized feed-forward mechanism driving bronchospasm via two distinct classes of G protein-coupled receptors (GPCRs) and provide a basis for reexamining α1AR inhibition for the management of stress/exercise-induced asthma and/or β2-agonist insensitivity in patients with difficult-to-control, disease subtypes.

Oral antibiotics relieve allergic asthma in post-weaning mice via reducing iNKT cells and function of ADRB2

“…In this study, we found that antibiotic therapy can increase the expression of Adrb2 . ADRB2 is expressed in bronchial smooth muscle cells ( 53 , 54 ) and bronchial epithelial cells, which contribute more RNA than dendritic cells during RNAseq. Testosterone has been reported to enhance β2 adrenergic receptor genome transcription, thereby increasing salbutamol relaxation in airway smooth muscle ( 55 ).…”