Cholinergic dilation of cerebral blood vessels is abolished in M5 muscarinic acetylcholine receptor knockout mice

Masahisa Yamada; Kathryn G. Lamping; Alokesh Duttaroy; Weilie Zhang; Yinghong Cui; Frank P. Bymaster; David L. McKinzie; Christian C. Felder; Chu-Xia Deng; Frank M. Faraci; Jürgen Wess

doi:10.1073/pnas.251542998

Back

Cholinergic dilation of cerebral blood vessels is abolished in M5 muscarinic acetylcholine receptor knockout mice

Journal article

Open access

Peer reviewed

Cholinergic dilation of cerebral blood vessels is abolished in M5 muscarinic acetylcholine receptor knockout mice

Masahisa Yamada, Kathryn G. Lamping, Alokesh Duttaroy, Weilie Zhang, Yinghong Cui, Frank P. Bymaster, David L. McKinzie, Christian C. Felder, Chu-Xia Deng, Frank M. Faraci, …

Proceedings of the National Academy of Sciences - PNAS, Vol.98(24), pp.14096-14101

11/13/2001

DOI: 10.1073/pnas.251542998

PMCID: PMC61174

PMID: 11707605

Files and links (1)

url

https://europepmc.org/articles/pmc61174View

Published (Version of record) Open Access

Abstract

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.

Biological Sciences

Details

Title: Subtitle: Cholinergic dilation of cerebral blood vessels is abolished in M5 muscarinic acetylcholine receptor knockout mice
Creators: Masahisa Yamada - National Institute of Diabetes and Digestive and Kidney Diseases
Kathryn G. Lamping
Alokesh Duttaroy
Weilie Zhang
Yinghong Cui
Frank P. Bymaster
David L. McKinzie
Christian C. Felder
Chu-Xia Deng
Frank M. Faraci
Jürgen Wess
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.98(24), pp.14096-14101
DOI: 10.1073/pnas.251542998
PMID: 11707605
PMCID: PMC61174
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 11/13/2001
Academic Unit: Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984303851002771

Metrics

14 Record Views

217 Times Cited - Web of Science