Recent Advances in β₂-Agonists for Treatment of Chronic Respiratory Diseases and Heart Failure

Abstract

β 2 -Adrenoceptor (β 2 -AR) agonists are widely used as bronchodilators. The emerge of ultralong acting β 2 -agonists is an important breakthrough in pulmonary medicine. In this review, we will provide mechanistic insights into the application of β 2agonists in asthma, chronic obstructive pulmonary disease (COPD), and heart failure (HF). Recent studies in β-AR signal transduction have revealed opposing functions of the β 1 -AR and the β 2 -AR on cardiomyocyte survival. Thus, β 2 -agonists and βblockers in combination may represent a novel strategy for HF management. Allosteric modulation and biased agonism at the β 2 -AR also provide a theoretical basis for developing drugs with novel mechanisms of action and pharmacological profiles. Overlap of COPD and HF presents a substantial clinical challenge but also a unique opportunity for evaluation of the cardiovascular safety of β 2 -agonists. Further basic and clinical research along these lines can help us develop better drugs and innovative strategies for the management of these difficult-to-treat diseases.

Chemical Synthesis of a Full-Length G-Protein-Coupled Receptor β2-Adrenergic Receptor with Defined Modification Patterns at the C-Terminus

“…Our strategy for the synthesis of β 2 AR 8P,Ub 7 is depicted in Figure 2a. β 2 AR 8P,Ub 7 was divided into four segments: β 2 AR 1−350 (2), β 2 AR 351−377,Aux,4P -NHNH 2 (8), Ub 1−75 -NHNH 2 (9), and β 2 AR 378−413,4P (5). NCL was chosen for the assembly of 8, 9, and 5 to give the C-terminal modified β 2 AR 351−413,8P,Ub -NHNH 2 (10).…”

“…G-protein-coupled receptors (GPCRs) are the largest class of signaling receptors in the human genome and are targeted by over 30% of modern pharmaceuticals. − One archetype GPCR is the β 2 adrenergic receptor (β 2 AR), which is targeted by respiratory and asthma drugs and has been extensively studied. − β 2 AR is a key mediator of cellular signaling in response to extracellular stimuli such as the hormones epinephrine and norepinephrine and can be coupled with downstream transducers, including Gs and Gi protein subtypes, GPCR kinases, and β-arrestins, to mediate a wide variety of physiological functions ranging from the control of vascular tone and cardiac performance to metabolism. − Recent studies revealed that post-translational modifications (e.g., phosphorylation and ubiquitination) at the C-terminal tail − can play essential roles in recruiting β-arrestin for β-arrestin dependent signaling and receptor internalization and regulating endocytic trafficking and degradation. , However, the exact mechanism of how β 2 AR post-translational modifications including phosphorylation and ubiquitination regulate receptor functions at the molecular level has yet to be fully elucidated, primarily because access to homogeneous samples of β 2 AR bearing a well-defined modified pattern is very difficult using either direct cellular expression or in vitro enzymatic methods …”

Cardiac arrhythmias in patients with bronchial asthma

“…Ранее в исследованиях показано, что постоянный прием препаратов для контроля БА увеличивает риск сердечно-сосудистых заболеваний [15,23]. Этот факт имеет большое клиническое значение при принятии решения о выборе базисной терапии больным БА, в особенности у больных старшего возраста.…”

Cardiac β-Adrenoceptor Signaling: The New Insight on An Old Target in the Therapy of Cardiovascular Disease

“…The β 1 -AR couples to G s protein while the β 2 -AR and the β 3 -AR couple to both G s and G i proteins [22]. The β 2 -AR can 'switch' its G protein-coupling preference from G s to G i and this is dependent on the phosphorylation of the β 2 -AR by PKA [23].…”

“…Agonist-induced receptor internalization is more rapid and obvious in β 2 -ARs, but less sensitive in β 1 -ARs [50]. Overall, homologous desensitization reduces G protein-mediated signal transduction, and is believed to produce a beneficial effect on the failing heart by restricting the β 1 -ARmediated cardiotoxic pathway [22], but it may also, to a lesser extent, contribute to the functional decline of the failing heart by causing β 2 -AR subsensitivity [39].…”