A multiplicity of muscarinic mechanisms: Enough signaling pathways to take your breath away

Since the classification by Dale of cholinergic responses as muscarinic or nicotinic and the subsequent identification of acetylcholine as the first neurotransmitter mediating the negative chronotropic response of cardiac muscarinic acetylcholine receptors (mAChR), studies on muscarinic receptors have provided a wealth of new insights that have had a wide impact on neurobiology and pharmacology. Muscarinic receptors are present in neurons in the central and peripheral nervous system, cardiac and smooth muscles, and a variety of exocrine glands. Mammals possess genes encoding five different subtypes of mAChR, termed M₁–M₅, which can be divided into two broad functional categories: the M₁, M₃, and M₅ receptors preferentially couple to the Gq family of G-proteins whereas the M₂ and M₄ receptors preferentially couple to the Gi family of G-proteins (1–3).

Muscarinic receptors in the airways are important both in the normal physiology and the pathophysiology of pulmonary function. Acetylcholine released from parasympathetic nerve terminals causes contraction of airway smooth muscle. Animals with asthma or other chronic inflammation of the airways exhibit hypersensitivity of the airways to muscarinic agonists, and muscarinic antagonists are used therapeutically in patients with asthma and chronic obstructive pulmonary disease (4, 5). The paper by Hansen et al. (6) in this issue of PNAS provides surprising information on at least one of the signaling mechanisms for the regulation of airway function by mAChR. These authors produced mice with a targeted mutation in the gene encoding phosphodiesterase 4D (PDE4D), one of a group of PDEs that have high specificity for hydrolysis of cAMP and are selectively inhibited by the drug rolipram. Inhibitors of type 4 PDEs exhibit anti-inflammatory actions and cause bronchodilation, suggesting that they may be useful in alleviating the symptoms of airway disorders (7). Hansen …