| Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice. | |
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MedLine Citation:
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PMID: 11707605 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The M(5) muscarinic receptor is the most recent member of the muscarinic acetylcholine receptor family (M(1)-M(5)) to be cloned. At present, the physiological relevance of this receptor subtype remains unknown, primarily because of its low expression levels and the lack of M(5) receptor-selective ligands. To circumvent these difficulties, we used gene targeting technology to generate M(5) receptor-deficient mice (M5R(-/-) mice). M5R(-/-) mice did not differ from their wild-type littermates in various behavioral and pharmacologic tests. However, in vitro neurotransmitter release experiments showed that M(5) receptors play a role in facilitating muscarinic agonist-induced dopamine release in the striatum. Because M(5) receptor mRNA has been detected in several blood vessels, we also investigated whether the lack of M(5) receptors led to changes in vascular tone by using several in vivo and in vitro vascular preparations. Strikingly, acetylcholine, a powerful dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5R(-/-) mice. This effect was specific for cerebral blood vessels, because acetylcholine-mediated dilation of extra-cerebral arteries remained fully intact in M5R(-/-) mice. Our findings provide direct evidence that M(5) muscarinic receptors are physiologically relevant. Because it has been suggested that impaired cholinergic dilation of cerebral blood vessels may play a role in the pathophysiology of Alzheimer's disease and focal cerebral ischemia, cerebrovascular M(5) receptors may represent an attractive therapeutic target. |
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Authors:
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M Yamada; K G Lamping; A Duttaroy; W Zhang; Y Cui; F P Bymaster; D L McKinzie; C C Felder; C X Deng; F M Faraci; J Wess |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2001-11-13 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 98 ISSN: 0027-8424 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2001 Nov |
Date Detail:
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Created Date: 2001-11-21 Completed Date: 2002-01-08 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 14096-101 Citation Subset: IM |
Affiliation:
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Laboratory of Bioorganic Chemistry National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylcholine
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metabolism,
pharmacology* Animals Arteries / drug effects Body Temperature / drug effects Brain / blood supply Cerebral Arteries / drug effects*, metabolism Corpus Striatum / drug effects, metabolism, pathology Dopamine / metabolism Mice Mice, Knockout Motor Activity / drug effects Muscarinic Agonists / pharmacology Oxotremorine / pharmacology Psychomotor Performance / drug effects Receptor, Muscarinic M5 Receptors, Muscarinic / genetics, metabolism, physiology* Salivation / drug effects Tremor |
| Grant Support | |
ID/Acronym/Agency:
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HL-38901/HL/NHLBI NIH HHS; HL-39050/HL/NHLBI NIH HHS; HL-62984/HL/NHLBI NIH HHS; NS-26421/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Muscarinic Agonists; 0/Receptor, Muscarinic M5; 0/Receptors, Muscarinic; 51-84-3/Acetylcholine; 70-22-4/Oxotremorine |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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