Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice

Title:
Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice
Authors:
Hamilton, Susan E.; Loose, Michael D.; Qi, Ming; Levey, Allan I.; Hille, Bertil; McKnight, G. Stanley; Idzerda, Rejean L.; Nathanson, Neil M.
Abstract:
Muscarinic acetylcholine receptors are members of the G protein-coupled receptor superfamily expressed in neurons, cardiomyocytes, smooth muscle, and a variety of epithelia. Five subtypes of muscarinic acetylcholine receptors have been discovered by molecular cloning, but their pharmacological similarities and frequent colocalization make it difficult to assign functional roles for individual subtypes in specific neuronal responses. We have used gene targeting by homologous recombination in embryonic stem cells to produce mice lacking the m1 receptor. These mice show no obvious behavioral or histological defects, and the m2, m3, and m4 receptors continue to be expressed in brain with no evidence of compensatory induction. However, the robust suppression of the M-current potassium channel activity evoked by muscarinic agonists in sympathetic ganglion neurons is completely lost in m1 mutant mice. In addition, both homozygous and heterozygous mutant mice are highly resistant to the seizures produced by systemic administration of the muscarinic agonist pilocarpine. Thus, the m1 receptor subtype mediates M current modulation in sympathetic neurons and induction of seizure activity in the pilocarpine model of epilepsy.
Citation:
Hamilton, Susan E., Michael D. Loose, Ming Qi, et al. 1997. "Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice." Proceedings of the National Academy of Sciences 94(24): 13311-13316.
Publisher:
National Academy of Sciences
DATE ISSUED:
1997
Department:
Neuroscience
Type:
Article
Additional Links:
http://www.pnas.org/content/94/24/13311.short
PERMANENT LINK:
http://hdl.handle.net/11282/606585

Full metadata record

DC FieldValue Language
dc.contributor.authorHamilton, Susan E.en
dc.contributor.authorLoose, Michael D.en
dc.contributor.authorQi, Mingen
dc.contributor.authorLevey, Allan I.en
dc.contributor.authorHille, Bertilen
dc.contributor.authorMcKnight, G. Stanleyen
dc.contributor.authorIdzerda, Rejean L.en
dc.contributor.authorNathanson, Neil M.en
dc.date.accessioned2016-04-22T12:38:21Zen
dc.date.available2016-04-22T12:38:21Zen
dc.date.issued1997en
dc.identifier.citationHamilton, Susan E., Michael D. Loose, Ming Qi, et al. 1997. "Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice." Proceedings of the National Academy of Sciences 94(24): 13311-13316.en
dc.identifier.urihttp://hdl.handle.net/11282/606585en
dc.description.abstractMuscarinic acetylcholine receptors are members of the G protein-coupled receptor superfamily expressed in neurons, cardiomyocytes, smooth muscle, and a variety of epithelia. Five subtypes of muscarinic acetylcholine receptors have been discovered by molecular cloning, but their pharmacological similarities and frequent colocalization make it difficult to assign functional roles for individual subtypes in specific neuronal responses. We have used gene targeting by homologous recombination in embryonic stem cells to produce mice lacking the m1 receptor. These mice show no obvious behavioral or histological defects, and the m2, m3, and m4 receptors continue to be expressed in brain with no evidence of compensatory induction. However, the robust suppression of the M-current potassium channel activity evoked by muscarinic agonists in sympathetic ganglion neurons is completely lost in m1 mutant mice. In addition, both homozygous and heterozygous mutant mice are highly resistant to the seizures produced by systemic administration of the muscarinic agonist pilocarpine. Thus, the m1 receptor subtype mediates M current modulation in sympathetic neurons and induction of seizure activity in the pilocarpine model of epilepsy.en
dc.language.isoen_USen
dc.publisherNational Academy of Sciencesen
dc.relation.urlhttp://www.pnas.org/content/94/24/13311.shorten
dc.subject.departmentNeuroscienceen_US
dc.titleDisruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in miceen_US
dc.typeArticleen
dc.identifier.journalProceedings of the National Academy of Sciencesen
dc.identifier.volume94en_US
dc.identifier.issue24en_US
dc.identifier.startpage13311en_US
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