Document Detail


Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice.
MedLine Citation:
PMID:  11707605     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
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:
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:
Created Date:  2001-11-21     Completed Date:  2002-01-08     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14096-101     Citation Subset:  IM    
Affiliation:
Laboratory of Bioorganic Chemistry National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetylcholine / 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:
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:
0/Muscarinic Agonists; 0/Receptor, Muscarinic M5; 0/Receptors, Muscarinic; 51-84-3/Acetylcholine; 70-22-4/Oxotremorine
Comments/Corrections

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