当前位置： SCI文献检索 > PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA期刊下所有文献 > Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation.

Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation.

Abstract：

:The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M(1) receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M(1) mAChR. BQCA reduces the concentration of ACh required to activate M(1) up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 microM. Furthermore studies in M(1)(-/-) mice demonstrates that BQCA requires M(1) to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M(1) allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces beta-arrestin recruitment to M(1), suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M(1) receptor and represents a promising therapeutic strategy for cognitive disorders.

journal_name

Proc Natl Acad Sci U S A

journal_title

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

authors

Ma L,Seager MA,Wittmann M,Jacobson M,Bickel D,Burno M,Jones K,Graufelds VK,Xu G,Pearson M,McCampbell A,Gaspar R,Shughrue P,Danziger A,Regan C,Flick R,Pascarella D,Garson S,Doran S,Kreatsoulas C,Veng L,Lindsley C

doi

10.1073/pnas.0900903106

subject

Has Abstract

pub_date

2009-09-15 00:00:00

pages

15950-5

issue

eissn

0027-8424

issn

1091-6490

pii

0900903106

journal_volume

106

pub_type

杂志文章

在线工具

Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation.