Beyond the dogma: novel β₂-adrenoceptor signalling in the airways

Abstract

b 2 -Adrenoceptor agonists evoke rapid bronchodilatation and are the mainstay of the treatment of asthma symptoms worldwide. The mechanism of action of this class of compounds is believed to involve the stimulation of adenylyl cyclase and subsequent activation of the cyclic adenosine monosphosphate (cAMP)/cAMP-dependent protein kinase cascade.This classical model of b 2 -adrenoceptor-mediated signal transduction is deeply entrenched, but there is compelling evidence that agonism of b 2 -adrenoceptors can lead to the activation of multiple effector pathways, which now compels researchers in academia and the pharmaceutical industry alike to think beyond the traditional dogma. Therefore, the regulation by b 2 -adrenoceptor agonists of responses, including airways smooth muscle tone and the secretory capacity of the epithelium and pro-inflammatory/immune cells, may be highly complex, involving both cAMPdependent and -independent mechanisms that, in many cases, may act in concert.In this article, the current status of b 2 -adrenoceptor-mediated signalling in the airways is reviewed in the context of understanding mechanisms that may underlie both the beneficial and detrimental effects of these drugs in asthma symptom management.

Effects of formoterol and salmeterol on cytokine release from monocyte-derived macrophages

“…Recently, it has been demonstrated that b-adrenoceptors can switch coupling from Gs to Gi [43]; however, since formoterol elevates cAMP in MDM, this is an unlikely explanation in MDM. Alternative b 2 -adrenoceptor signalling pathways have been proposed [44,45]. For example, b 2 -adrenoceptors coupling to Gs can mediate smooth muscle relaxation in a cAMP-independent manner [46,47].…”

Pharmacological Characterization of Abediterol, a Novel Inhaled β2-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models

“…␤ 2 -Adrenoceptor agonists act by binding to the ␤ 2 -adrenoceptor, which activates adenylate cyclase via the signal-transducing G s protein, thereby enhancing cellular cAMP levels and activating protein kinase A. One of the consequences of this signaling is a fall in intracellular calcium and the promotion of smooth muscle relaxation (Giembycz and Newton, 2006). Apart from the affinity for ␤ 2 -receptors, the potency of agonists also depends on the intrinsic efficacy of each compound.…”

Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism

“…It is well-established that the β 2 -adrenoceptor can couple via the heterotrimeric stimulatory G-protein (Gs) to adenylyl cyclase (AC) [22]. To evaluate, whether adenylyl cyclase is involved in the action of salbutamol, we employed a pharmacological inhibitor of adenylyl cyclase, SQ-22,536.…”

“…large-conductance calcium activated potassium channel and ATP-sensitive potassium channel) that open upon phosphorylation, resulting in the efflux of K + from the cell down its concentration gradient leading to membrane rectification (repolarisation). Gating of K + channels may also be effected by the direct interaction of G sα with the channel independently of cAMP and PKA [22]. Pharmacological blockade of large-conductance channel (BK Ca ) with charybdotoxin, and the more selective iberiotoxin, prevents hyperpolarisation and β 2 -adrenoceptor-mediated relaxation in smooth muscle cells [22].…”

“…Gating of K + channels may also be effected by the direct interaction of G sα with the channel independently of cAMP and PKA [22]. Pharmacological blockade of large-conductance channel (BK Ca ) with charybdotoxin, and the more selective iberiotoxin, prevents hyperpolarisation and β 2 -adrenoceptor-mediated relaxation in smooth muscle cells [22]. To evaluate, whether BK Ca channels have a role in salbutamol-induced survival of human eosinophils, the effect of salbutamol was tested in the presence and absence of charybdotoxin and iberiotoxin.…”