Selective activation of the M 1 muscarinic acetylcholine receptor achieved by allosteric potentiation
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...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 37; pp. 15950 - 15955 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
15.09.2009
|
Online Access | Get full text |
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Summary: | 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 μM. 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 β-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. |
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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0900903106 |