Acetylcholine released from vagal nerve endings constricts airways by stimulating M3 muscarinic receptors on the airway smooth muscle. At the same time, released acetylcholine feeds back onto inhibitory M2 muscarinic autoreceptors on the nerve endings, limiting further release of acetylcholine. Loss of function of these M2 receptors increases vagally-mediated bronchoconstriction after viral airway infections, exposure to ozone, or antigen inhalation. Viral infections may decrease M2 receptor function by inducing inflammation or via direct damage to the receptors as a result of cleavage of sialic acid residues by viral neuraminidase. Inflammation appears to be critical in the loss of M2 receptor function after ozone exposure. Antigen-induced loss of M2 receptor function can be reversed acutely by administering the poly-anionic substances heparin or poly-l-glutamate, possibly by binding and neutralizing positively charged eosinophil proteins. Such positively charged eosinophil proteins, particularly major basic protein, may be acting as endogenous inhibitors at the M2 receptors, as can be demonstrated in in vitro ligand binding studies.
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