β2-adrenoceptor (β2-AR) agonists are the primary bronchodilator treatments used to treat obstructive lung conditions such as COPD and asthma [1]. These conditions are associated with elevated cholinergic nerve activity [2] and it is recognised that β2-AR agonists inhibit cholinergic contractions of airway smooth muscle (ASM), however the cellular mechanisms underlying their effects are still unclear. Contractions of ASM induced by release of acetylcholine (ACh) from cholinergic nerves are thought to result from activation of postjunctional M3 muscarinic receptors (M3Rs) [3]. ASM also has an abundance of post-junctional M2Rs, which outnumber the M3Rs by a ratio of 4:1 in some species [3], yet their contribution to cholinergic nerve-induced contractions of ASM is poorly understood. β-ARs couple to Gs-proteins which activate adenylate cyclase and elevate cytosolic cAMP levels, while activation of M2Rs leads to a reduction inadenylate cyclase activity. Therefore, it was generally considered that the role of M2Rs on ASM was confined to offsetting relaxations induced by activation of β2-ARs. Recently, Alkawadriet al. (2021) reported a profound M2R-mediated hypersensitisation of M3R-dependent contractions of murine ASM, indicating that activation of postjunctional M2Rs made a greater contribution to cholinergic nerve-mediated contractions of ASM than previously realised [4]. This raised the possibility that the bronchodilator effects of β-AR agonists could involve inhibition of M2R-dependent contractions of ASM. Studies on murine ASM revealed that M2R-dependent contractions, induced by electric field stimulation (EFS) or the cholinergic agonist carbachol, were inhibited by the β-AR agonist denopamine, and that these effects were reduced in bronchial ring preparations taken from M2R KO mice [5]. Our data fit with the model that postjunctional M2Rs are involved in the bronchoconstrictor effects of ACh and that the therapeutic effects of b-AR agonists in the treatment of asthma and COPD may involve inhibition of M2R-dependent contractions of ASM.
Command and Control: Unveiling the Regulation of Smooth Muscle Function (Dundalk Institute of Technology, Ireland) (2024) Proc Physiol Soc 58, SA08
Research Symposium: Unravelling the role of post-junctional M2Rs in ASM contractions and their regulation by β-AR agonists.
Tuleen Alkawadri1, Mark Hollywood1, Keith Thornbury1, Gerard Sergeant1,
1Dundalk Institute of Technology Dundalk Ireland,
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Where applicable, experiments conform with Society ethical requirements.