Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M ₃ subtype

Abstract

Muscarinic acetylcholine receptors consist of five distinct subtypes and have been important targets for drug development. In the periphery, muscarinic acetylcholine receptors mediate cholinergic signals to autonomic organs, but specific physiological functions of each subtype remain poorly elucidated. Here, we have constructed and analyzed mutant mice lacking the M3 receptor and have demonstrated that this subtype plays key roles in salivary secretion, pupillary constriction, and bladder detrusor contractions. However, M 3-mediated signals in digestive and reproductive organs are dispensable, likely because of redundant mechanisms through other muscarinic acetylcholine receptor subtypes or other mediators. In addition, we have found prominent urinary retention only in the male, which indicates a considerable sex difference in the micturition mechanism. Accordingly, this mutant mouse should provide a useful animal model for investigation of human diseases that are affected in the peripheral cholinergic functions.

Impaired contractility and detrusor hypertrophy in cavin-1-deficient mice

“…A difference between males and females with regard to structural changes in the bladder has previously been reported for mice that lack the muscarinic M 3 14 receptor. In those mice, the response to carbachol was eliminated in both males and females (3 x 10-8 →3x10-3 M); yet only male mice had enlarged bladders and mild hydronephrosis (Matsui et al, 2000). Such differences may relate to the higher bladder outlet resistance in males.…”

Vascular and metabolic effects of methacholine in relation to insulin action in muscle

“…These receptors are able to vasodilate using NOdependent and NO-independent endothelial hyperpolarising factor-mediated mechanisms [38]. However, although mice lacking M3 subtype receptors have been generated [39], it has not been reported that these animals have defects relevant to glucose homeostasis, even though they lack smooth muscle contraction response to cholinergic agonists [40].…”

Antimuscarinic antibodies in Sjögren's syndrome: Where are we, and where are we going?

“…The textbook description (44) of the control of secretion outlines a linear sequence of events, as follows: ACh binds to and activates M 3 R, the G protein-coupled muscarinic type 3 ACh receptor (45,46) (action 1 in Figure 1. Western blot identification of the human M 3 muscarinic receptor (M 3 R).…”

“…It is well established from radioligand binding studies that, in both the bladder and the colon, the muscarinic receptor population primarily comprises the M 2 R and M 3 R subtypes, in a mixture of ϳ80%:20% (60). Although M 2 R is the predominant receptor subtype present, work with knockout mice has confirmed that M 3 R is the receptor subtype that mediates the majority of the contractile response in smooth muscle (46,61). Accordingly, if present, antimuscarinic antibodies should be able to disrupt the function of the smooth muscle within the bladder and the colon and could therefore account for the extraglandular symptoms of SS.…”