Evidence for M2 and M3 Muscarinic receptor involvement in cholinergic excitatory junction potentials through synergistic activation of Cation channels in the longitudinal muscle of mouse ileum

Cholinergic nerve-mediated excitatory junction potentials (ejps) in the longitudinal muscle of mouse ileum were characterized by using m2 or m3 muscarinic receptor-knockout (ko) mice and 1-[β-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl]-1h-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 m2-mediated pathways linked to cation channel activation. in m2-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 m3-ko as well as m2/m3 double-ko preparations. the results suggest that the wildtype cholinergic ejp is not a simple mixture of m2 and m3 responses,but due to synergistic activation of cation channels by both m2 and m3 receptors in the murine ileal longitudinal muscle. © the japanese pharmacological society.