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Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice.

Members of the muscarinic acetylcholine receptor family (M1-M5) are known to be involved in a great number of important central and peripheral physiological and pathophysiological processes. Because of the overlapping expression patterns of the M1-M5 muscarinic receptor subtypes and the lack of ligands endowed with sufficient subtype selectivity, the precise physiological functions of the individual receptor subtypes remain to be elucidated. To explore the physiological roles of the M2 muscarinic receptor, we have generated mice lacking functional M2 receptors by using targeted mutagenesis in mouse embryonic stem cells. The resulting mutant mice were analyzed in several behavioral and pharmacologic tests. These studies showed that the M2 muscarinic receptor subtype, besides its well documented involvement in the regulation of heart rate, plays a key role in mediating muscarinic receptor-dependent movement and temperature control as well as antinociceptive responses, three of the most prominent central muscarinic effects. These results offer a rational basis for the development of novel muscarinic drugs.

Pubmed ID: 9990086

Authors

  • Gomeza J
  • Shannon H
  • Kostenis E
  • Felder C
  • Zhang L
  • Brodkin J
  • Grinberg A
  • Sheng H
  • Wess J

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 16, 1999

Associated Grants

None

Mesh Terms

  • Analgesia
  • Animals
  • Brain
  • Embryo, Mammalian
  • Female
  • Gene Expression
  • Genomic Library
  • Homozygote
  • In Situ Hybridization
  • Male
  • Mice
  • Mice, Knockout
  • Morphine
  • Mutagenesis, Site-Directed
  • Organ Specificity
  • Oxotremorine
  • Pain
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic
  • Restriction Mapping
  • Salivation
  • Stem Cells
  • Tremor