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Quantitative analysis of the loss of muscarinic receptors in various peripheral tissues in M 1 –M 5 receptor single knockout mice
Author(s) -
Ito Yoshihiko,
Oyunzul Luvsandorj,
Seki Masanao,
Fujino Oki Tomomi,
Matsui Minoru,
Yamada Shizuo
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00113.x
Subject(s) - endocrinology , medicine , muscarinic acetylcholine receptor , chemistry , receptor , submandibular gland , knockout mouse , muscarinic acetylcholine receptor m3 , muscarinic acetylcholine receptor m2 , biology
Background and purpose: To compare loss in binding to muscarinic receptor (mAChR) subtypes with their known functions, the total density of muscarinic receptors was measured in peripheral tissues from wild type (WT) and mAChR knockout (KO) mice. Experimental approach: Binding parameters of [N‐methyl‐ 3 H]scopolamine methyl chloride ([ 3 H]NMS) were determined in 10 peripheral tissues of WT and M 1 –M 5 receptor KO mice. Competition between [ 3 H]NMS and darifenacin (selective M 3 receptor antagonist) was also measured Key results: There was an extensive loss of [ 3 H]NMS‐binding sites (maximal number of binding sites, B max ) in heart and smooth muscle from M 2 KO mice, compared with WT mice. Smooth muscle from M 3 KO mice also showed a moderate loss of B max . B max fell in pancreas and bladder of M 4 KO mice and in prostate in M 1 KO and M 3 KO mice. There was a large loss of B max in exocrine and endocrine glands of M 3 KO mice with a moderate decrease in M 2 KO mice. Darifenacin inhibited specific [ 3 H]NMS binding in submandibular gland and bladder of WT, M 2 KO and M 3 KO mice. K i (inhibition constant) values for darifenacin in the submandibular gland were the same in WT and M 2 KO mice but increased in M 3 KO mice. However, K i values in bladder were decreased in M 2 KO mice and increased in M 3 KO mice. Conclusions and implications: Single mAChR KO mice exhibit a loss of mAChR in peripheral tissues that generally paralleled the reported loss of function. Quantitative analysis of data, however, also suggested that, in some instances, normal expression of a receptor subtype depended on expression of other subtypes.