Muscarinic Receptors and Control of Airway Smooth Muscle

Contraction of airway smooth muscle is mediated by M3 muscarinic receptors on the airway smooth muscle. However, there is no evidence suggesting that hyperresponsiveness results from any alterations in function of these M3 muscarinic receptors. In contrast, there is clearly increased release of the neurotransmitter acetylcholine in animal models of hyperactivity and in asthma. Release of acetylcholine is controlled by inhibitory M2 muscarinic receptors, and it appears that it is these M2 receptors that are dysfunctional in animal models of hyperresponsiveness. Allergen-induced M2 receptor dysfunction is absolutely dependent upon an influx of eosinophils into the airways. Activated eosinophils release major basic protein, which binds to M2 receptors and prevents binding of acetylcholine. Thus, the normal negative feedback control of acetylcholine release is lost, and acetylcholine release is increased. In conclusion, loss of function of inhibitory M2 muscarinic receptors on the airway parasympathetic nerves causes vagally mediated bronchoconstriction and hyperresponsiveness following antigen challenge.