Further characterization of the synergistic activation mechanism of cationic channels by M₂ and M₃ muscarinic receptors in mouse intestinal smooth muscle cells.

In mouse ileal myocytes, muscarinic receptor-mediated cationic current (mI) occurs mainly through synergism of M₂ and M₃ subtypes involving G_i/o-type GTP-binding proteins and phospholipase C (PLC). We have further studied the M₂/M₃ synergistic pathway. Carbachol-induced mI was markedly depressed by YM-254890, a G_q/11 protein inhibitor. However, the mI was unaffected by heparin, calphostin C, or chelerythrine, suggesting that mI activation does not involve signaling molecules downstream of phosphatidylinositol 4,5-bisphosphate (PIP₂) breakdown. M₂-knockout (KO) mice displayed a reduced mI (~10% of wild-type mI) because of the lack of M₂-G_i/o signaling. The impaired mI was insensitive to neuropeptide Y possessing a G_i/o-stimulating activity. M₃-KO mice also displayed a reduced mI (~6% of wild-type mI) because of the lack of M₃-G_q/11 signaling, and the mI was insensitive to prostaglandin F_2α possessing a G_q/11-stimulating activity. These results suggest the importance of G_q/11/PLC-hydrolyzed PIP₂ breakdown itself in mI activation and also support the idea that the M₂/M₃ synergistic pathway represents a signaling complex consisting of M₂-G_i/o and M₃-G_q/11-PLC systems in which both G proteins are special for this pathway but not general in receptor coupling.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}