Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable.
Cholinergic agents elicit prominent smooth muscle contractions via stimulation of muscarinic receptors that comprise five distinct subtypes (M1-M5). Although such contractions are important for autonomic organs, the role of each subtype has not been characterized precisely because of the poor selectivity of the currently available muscarinic ligands. Here, we generated a mutant mouse line (M2-/-M3-/- mice) lacking M2 and M3 receptors that are implicated in such cholinergic contractions. The relative contributions of M2 and M3 receptors in vitro was approximately 5 and 95% for the detrusor muscle contraction and approximately 25 and 75% for the ileal longitudinal muscle contraction, respectively. Thus, M1, M4, or M5 receptors do not seem to play a role in such contractions. Despite the complete lack of cholinergic contractions in vitro, M2-/-M3-/- mice were viable, fertile, and free of apparent intestinal complications. The urinary bladder was distended only in males, which excludes a major contribution by cholinergic mechanisms to the urination in females. Thus, cholinergic mechanisms are dispensable in gastrointestinal motility and female urination. After 10 Hz electrical field stimulation, noncholinergic inputs were found to be increased in the ileum of M2-/-M3-/- females, which may account for the lack of apparent functional deficits. Interestingly, the M2-/-M3-/- mice had smaller ocular pupils than M3-deficient mice. The results suggest a novel role of M2 in the pupillary dilation, contrary to the well known cholinergic constriction. These results collectively suggest that an additional mechanism operates in the control of pupillary constriction-dilatation.
Matsui
Minoru
M
Division of Neuronal Network, Department of Basic Medical Sciences, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. mmatsui@dd.iij4u.or.jp
Motomura
Daisuke
D
Fujikawa
Toru
T
Jiang
Jian
J
Takahashi
Shin-ichi
S
Manabe
Toshiya
T
Taketo
Makoto M
MM
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004064:Digestive System / Q000033:anatomy & histology; D004558:Electric Stimulation; D005260:Female; D018390:Gene Targeting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015877:Miosis / Q000473:pathology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D011680:Pupil / Q000502:physiology; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000235:genetics / Q000502:physiology*; D012737:Sex Factors; D016019:Survival Analysis; D016055:Urinary Retention / Q000175:diagnosis / Q000209:etiology
D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D002217:Carbachol