Muscarinic Regulation of Gastrointestinal Motility

In the mammalian gastrointestinal tract, acetylcholine is the primary excitatory neurotransmitter that binds to and stimulates muscarinic receptors to regulate the contractile activity of gastrointestinal smooth muscles. There are five subtypes of muscarinic receptors. In gastrointestinal smooth muscles, at least two muscarinic receptors, M2 and M3, are the major subtypes. Several types of antagonists have been used to explore the role of each muscarinic receptor subtype in visceral smooth muscles. However, these receptor antagonists present challenges with receptor subtype selectivity. The acetylcholine-binding site of the muscarinic receptor has a similar structure in each subtype, and developing selective antagonists for each subtype is extremely difficult. Therefore, caution should be given when interpreting the results of studies using subtype antagonists. Recent studies using muscarinic receptor knockouts have established the role of each subtype in the contractile responses of gastrointestinal smooth muscles. For example, at lower agonist concentrations, both the M2 and M2/M3 receptor complexes activate certain types of cation channels and elicit smooth muscle contraction, whereas at higher agonist concentrations, M3 receptor function becomes dominant in ileal smooth muscles. Considering the results of previous studies, the roles of the M2 and M3 subtypes appear to differ depending on the site and tissue of the gastrointestinal tract. In this chapter, we outlined functional approaches in vitro, ex vivo and in vivo using M2 and M3 receptor knockout mice to elucidate the role of M2 and M3 subtypes on regulation of the gastrointestinal motility and its underlying mechanisms mediated by each subtype.