Effect of inflammatory cell mediators on M₂ muscarinic receptors in the lungs

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.