Epinephrine evokes shortening of human airway smooth muscle cells following β<sub>2</sub>adrenergic receptor desensitization
B.T. Deeney, Gaoyuan Cao, S. Orfanos, Jordan Lee, Mengyuan Kan, Blanca E. Himes, Vishal Parikh, Cynthia Koziol‐White, Steven S. An, Reynold A. Panettieri
Abstract
Epinephrine (EPI), an endogenous catecholamine involved in the body’s fight-or-flight responses to stress, activates α 1 -adrenergic receptors (α 1 ARs) expressed on various organs to evoke a wide range of physiological functions, including vasoconstriction. In the smooth muscle of human bronchi, however, the functional role of EPI on α 1 ARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating β 2 -adrenergic receptors (β 2 ARs). Conventionally, the selective β 2 AR agonism of EPI was thought to be, in part, due to a predominance of β 2 ARs and/or a sparse, or lack of α 1 AR activity in human airway smooth muscle (HASM) cells. Surprisingly, we find that HASM cells express a high abundance of ADRA1B (the α 1 AR subtype B) and identify a spontaneous “switch-like” activation of α 1 ARs 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 β 2 ARs and/or under experimental conditions that induce β 2 AR tachyphylaxis. EPI-induced procontractile effects were abrogated by an α 1 AR 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 α 1 AR inhibition for the management of stress/exercise-induced asthma and/or β 2 -agonist insensitivity in patients with difficult-to-control, disease subtypes.