The functional roles of M2 and M3 subtypes of muscarinic receptors in the gut studied with receptor knockout mice.

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In the present study, we have used M_2 or M_3 single knockout (KO) and M_2/M_3-double KO mice as experimental tools, aiming to identify muscarinic signaling pathways leading to the contraction of intestinal smooth muscles and to elucidate the role of M_2 and M_3 receptors in the processes. The summarized results are as follows : 1) Analysis of the contractile responses to exogenously applied the muscarinic agonist carbachol or cholinergic nerve stimulation in ileal and gastric smooth muscles revealed that both M_2 and M_3 subtypes, via different signal transduction mechanisms, participate in mediating contractions with the latter subtype assuming a greater role (Unno et al., 2005 ; 2006 ; Kitazawa et al., 2007). 2) Using the patch clamp techniques, we have demonstrated that the activation of muscarinic cationic channels requires stimulation of both M_2 and M_3 subtypes in such a way that M_3 receptor permissively opens the channels, and M_2 receptor synergistically transmits the open state to a long-lasting mode (Okamoto et al., 2004 ; Sakamoto et al., 2006 ; Unno et al., 2006 ; Sakamoto et al., 2007). These results provide novel insights into the regulation of visceral smooth muscle cationic channel activity. 3) We have also studied the role of M_2 and M_3 subtypes in the regulations of voltage-gated Ca^<2+> channel activity, Ca^<2+> sensitivity to contractile proteins and peristaltic movement, and we are now preparing the manuscripts.