title: M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system.
abstract: A large body of evidence indicates that muscarinic acetylcholine receptors (mAChRs) play critical roles in regulating the activity of many important functions of the central and peripheral nervous systems. However, identification of the physiological and pathophysiological roles of the individual mAChR subtypes (M(1)-M(5)) has proven a difficult task, primarily due to the lack of ligands endowed with a high degree of receptor subtype selectivity and the fact that most tissues and organs express multiple mAChRs. To circumvent these difficulties, we used gene targeting technology to generate mutant mouse lines containing inactivating mutations of the M(1)-M(5) mAChR genes. The different mAChR mutant mice and the corresponding wild-type control animals were subjected to a battery of physiological, pharmacological, behavioral, biochemical, and neurochemical tests. The M(1)-M(5) mAChR mutant mice were viable and reproduced normally. However, each mutant line displayed specific functional deficits, suggesting that each mAChR subtype mediates distinct physiological functions. These results should offer new perspectives for the rational development of novel muscarinic drugs.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA. jwess@helix.nih.gov
authors.forename: J
authors.initials: J
authors.lastname: Wess
authors.forename: A
authors.initials: A
authors.lastname: Duttaroy
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Gomeza
authors.forename: Y
authors.initials: Y
authors.lastname: Cui
authors.forename: T
authors.initials: T
authors.lastname: Miyakawa
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: L
authors.initials: L
authors.lastname: McKinzie
authors.forename: C C
authors.initials: CC
authors.lastname: Felder
authors.forename: K G
authors.initials: KG
authors.lastname: Lamping
authors.forename: F M
authors.initials: FM
authors.lastname: Faraci
authors.forename: C
authors.initials: C
authors.lastname: Deng
authors.forename: M
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004827:Epilepsy / Q000235:genetics; D006321:Heart / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000502:physiology; D011976:Receptors, Muscarinic / Q000235:genetics* / Q000502:physiology
chemical_list: D011976:Receptors, Muscarinic