Current issues with beta2-adrenoceptor agonists: pharmacology and molecular and cellular mechanisms.
Beta2-adrenoceptors are widely, almost ubiquitously, expressed. Activation of these receptors on bronchial smooth muscle by short- and long-acting beta2-adrenoceptor agonists causes bronchodilation. Here, the beta2-adrenoceptor is linked by the G protein, Gs, to adenylyl cyclase, which increases cyclic adenosine monophosphate (cAMP), thus activating protein kinase A, which affects calcium levels and reduces the efficiency of myosin light-chain kinase, causing relaxation. Activation also entrains numerous acute and longer term downregulation responses affecting the number, location, and net efficiency of signaling of the receptor. Synthetic beta2-agonists are all "partial agonists," incompletely able to optimally stimulate cAMP signal transduction. However, compared with some cells (such as mast cells) involved in exercise- induced asthma induction, airway smooth muscle is privileged in that transduction efficiency is intrinsically high and the tissue is very resistant to complete downregulation. Glucocorticosteroids have broadly beneficial interactions with beta2-adrenoceptors. Researchers have recently discovered that the beta2-adrenoceptor may function as a homodimer and that it can form heterodimers with both the beta1- and beta3-adrenoceptors, and possibly other receptors. This further complicates interpretation of the effect of beta2-adrenoceptor polymorphisms, but it is unknown whether this occurs in humans in vivo. Researchers have known for some time that strong contraction involving receptors coupled to the Gq G protein (e.g., cholinergic and leukotriene receptors via negative biochemical crosstalk), virus infection (via uncoupling), and inflammation (via kinases) can impair relaxation. Most recently, researchers have discovered that the beta2-adrenoceptor can also send potentially adverse signals after "atypical coupling" to Gq rather than Gs. The clinical implications of these uncouplings, crosstalk, and atypical coupling possibilities are not well-understood.
Anderson
Gary P
GP
Lung Disease Research Group, Cooperative Research Centre for Chronic Inflammatory Diseases, Departments of Medicine and Pharmacology, The University of Melbourne, Parkville, Australia. gpa@unimelb.edu.au <gpa@unimelb.edu.au>
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000494:pharmacology; D006801:Humans; D015398:Signal Transduction / Q000502:physiology
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents