Beta2 adrenergic receptors in asthma: A current perspective

Abstract

The role of the beta 2-adrenergic receptor in both the pathogenesis and treatment of asthma has been a subject of intense speculation and investigation for 25 years. The physiological effects of endogenous circulating catecholamines and exogenous adrenergic agonists in the lung are mediated by the beta 2-adrenergic receptor, which is present on a variety of cell types. Documented effects of beta 2-adrenergic receptor activation in the human lung include smooth muscle relaxation, inhibition of acetylcholine release from cholinergic nerve terminals, stimulation of serous and mucous cell secretion, increases in ciliary beat frequency, promotion of water movement into the airway lumen by stimulation of ion secretion across the apical membrane of epithelial cells, increase in bronchial blood flow, reduction in venular permeability, and inhibition of mediator release from some, but not all, inflammatory cells. Beta 2-Adrenergic receptors are present in normal or increased numbers on asthmatic airway smooth muscle but are uncoupled in severe asthma, leading to functional hyporesponsiveness, probably due to the effects of inflammatory mediators. There is also evidence for dysfunction of beta 2-adrenergic receptors on circulating inflammatory cells following mediator release. However, dysfunction of the receptors on airway smooth muscle and inflammatory cells is unlikely to be of primary importance in the pathogenesis of asthma. There is increasing concern that regular beta 2-adrenergic receptor agonist use in the therapy of asthma is deleterious. Although a number of theories have been advanced to explain such an effect, none is well established and further research is urgently required.

Ligand-Specific Interactions Modulate Kinetic, Energetic, and Mechanical Properties of the Human β2 Adrenergic Receptor

“…The β 2 receptor mainly resides in smooth muscles (Barnes, 1993), binds the hormones adrenalin and noradrenalin, and is involved in regulating cardiovascular and pulmonary function. Several ligands that bind to β 2 AR are used as drugs in cardiac disease and asthma treatment (Bai, 1992). Investigating the interactions established by ligands and understanding the effect of ligand-binding on the dynamic energy landscape of the receptor might help to improve the development of more efficient drugs.…”

Localization of β1-Adrenergic Receptors in the Cochlea and the Vestibular Labyrinth

“…For example, β 1 -AR increase heart rate and force and β 2 -AR open and moisturize airways and eyes [2,26]. Hearing and the sensation of balance and acceleration may be as important as sight for a successful "fight or flight reaction".…”

Cholesterol increases kinetic, energetic, and mechanical stability of the human β2-adrenergic receptor

“…Together with its close relative β 1 AR, β 2 AR senses adrenalin in bronchial vasculature and noradrenalin in cardiac muscle. The implication in a broad spectrum of diseases, like asthma or heart failure, makes β 2 AR a potential therapeutic target (3)(4)(5)(6)(7). Several crystal structures of β 2 AR have been determined during the last years (8)(9)(10)(11)(12), providing unique insights into the structure-function relationship of GPCRs.…”