Muscarinic receptors and control of airway smooth muscle

Contraction of airway smooth muscle is mediated by M-3 muscarinic receptors on the airway smooth muscle. However, there is no evidence suggesting that hyperresponsiveness results from any alterations in function of these M-3 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 M-2 muscarinic receptors, and it appears that it is these M-2 receptors that are dysfunctional in animal models of hyperresponsiveness. Allergen-induced M-2 receptor dysfunction is absolutely dependent upon an influx of eosinophils into the airways. Activated eosinophils release major basic protein, which binds to M-2 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 M-2 muscarinic receptors on the airway parasympathetic nerves causes vagally mediated bronchoconstriction and hyperresponsiveness following antigen challenge.