M3 muscarinic receptor-deficient mice retain bethanechol-mediated intestinal ion transport and are more sensitive to colitis.
Acetylcholine (ACh) is an important regulator of intestinal epithelial ion transport via muscarinic or nicotinic ACh receptors. Previous studies emphasize the role of the M3 muscarinic receptor subtype in mediating the effects of cholinergic agonists on intestinal ion transport. With the prevalence of mouse models to study intestinal (patho)physiology, it is crucial that ion transport be understood in this species. Using M3 receptor-deficient (KO) mice and wild-type (WT) mice, we examined M3 receptor contributions to ion transport as well as its role in colitis induced by dextran sodium sulphate (DSS). In the Ussing chambers, ileal and colonic tissue from M3 KO and WT mice displayed similar baseline ion transport properties. Short-circuit current (ISC) responses to the muscarinic receptor agonist bethanechol were slightly decreased in ileal tissue from M3 KO mice compared with tissue from WT mice, whereas responses were not significantly different in colonic tissue. ISC responses to bethanechol were partially inhibited by pirenzepine in WT ileum, but not tetrodotoxin, suggesting involvement of a non-neuronal M1 muscarinic receptor. In the ileum, the M3 receptor may inhibit neuronally evoked ion transport, as indicated by the increased ISC responses to electrical stimulation in tissue from M3 KO mice. Furthermore, whereas all DSS-treated mice developed colitis, M3 KO mice displayed more rapid mass loss and more severe disease than DSS-treated WT mice, even following a reduction in the amount and time of DSS treatment. Thus, M3 receptor-KO mice are compensated in their ability to evoke muscarinic receptor-driven ion transport responses, but are more sensitive to DSS. This work highlights the need to dissect muscarinic receptor-mediated events in the mouse, as mice become increasingly valuable in enteric disease models.
Hirota
Christina L
CL
Intestinal Disease Research Programme, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada.
McKay
Derek M
DM
D000818:Animals; D018723:Bethanechol / Q000494:pharmacology*; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010890:Pirenzepine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043643:Receptor, Muscarinic M1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D018723:Bethanechol; D010890:Pirenzepine; D016264:Dextran Sulfate