Cholinergic nerve–mediated excitatory junction potentials (EJPs) in the longitudinal muscle of mouse ileum were characterized by using M
2 or M
3 muscarinic receptor–knockout (KO) mice and 1-[
β-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl]-1
H-imidazole hydrochloride (SK&F 96365) and pertussis toxin (PTX). EJPs evoked by electrical field stimulation (EFS) in wild-type preparations, initially determined to be cholinergic in origin using tetrodotoxin, atropine, and eserine, were profoundly depressed after SK&F 96365 treatment known to block muscarinic receptor–operated cation channels. A similar depression of the EJPs was also observed by PTX treatment, which is predicted to disrupt M
2-mediated pathways linked to cation channel activation. In M
2-KO mouse preparations, cholinergic EJPs were evoked by EFS with their relative amplitude of 20% – 30% to the wild-type EJP and strongly inhibited by SK&F 96365. No cholinergic EJP was seen in M
3-KO as well as M
2/M
3 double-KO preparations. The results suggest that the wild-type cholinergic EJP is not a simple mixture of M
2 and M
3 responses, but due to synergistic activation of cation channels by both M
2 and M
3 receptors in the murine ileal longitudinal muscle.
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