Activation of M(2) muscarinic receptors in guinea-pig ileum opens cationic channels modulated by M(3) muscarinic receptors

In longitudinal muscle of guinea-pig ileum, activation of muscarinic receptors causes contraction antagonised by M(3) receptor subtype antagonists despite a preponderance of M(2) receptor subtype binding sites. Experiments on single smooth muscle cells under voltage-clamp described here show that the cationic current evoked by carbachol which normally causes depolarization of the muscle is inhibited competitively by M(2) antagonists with affinities typical of antagonism at a M(2) receptor. However, M(3) antagonists strongly reduced the maximum cationic current which could be evoked by carbachol in a non-competitive manner with affinities typical for an action at M(3) receptors. Thus cation channels are gated by M(2) receptor activation but strongly modulated by activation of M(3) receptors.