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The M3-muscarinic receptor regulates memory and learning in a receptor phosphorylation/arrestin-dependent manner.

Poulin, Benoit, Butcher, Adrian, McWilliams, Phillip, Bourgognon, Julie-Myrtille, Pawlak, Robert, Bottrill, Andrew, Mistry, Sharad, Wess, Jurgen, Rosethorne, Liz, Charlton, Steven and Tobin, Andrew (2010) The M3-muscarinic receptor regulates memory and learning in a receptor phosphorylation/arrestin-dependent manner. Proceedings of the National Academy of Sciences, 107 (20). pp. 9440-9445. ISSN 0027-8424


Degeneration of the cholinergic system is considered to be the underlying pathology that results in the cognitive deficit in Alzheimer’s disease. This pathology is thought to be linked to a loss of signalling through the cholinergic M1-muscarinic receptor subtype. However, recent studies have cast doubt on whether this is the primary receptor mediating cholinergic-hippocampal memory and learning. We demonstrate here that M3-muscarinic receptor knockout mice show a deficit in fear conditioning memory and learning. The mechanism employed by the M3-muscarinic receptor in this process involves receptor phosphorylation since a transgenic mouse strain expressing a phosphorylation deficient receptor mutant also shows a deficit in the fear conditioning. Consistent with a role for receptor phosphorylation we demonstrate that the M3-muscarinic receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation deficient M3-muscarinic receptor was coupled normally to Gq/11-signalling but was uncoupled from phosphorylation-dependent processes such as receptor internalisation and arrestin recruitment. It can, therefore, be concluded that the mechanism adopted by the M3-muscarinic receptor to mediate memory and learning is independent of G-protein coupling but dependent on receptor phosphorylation/arrestin-mediated processes. This study opens the potential for biased ligands to the M3-muscarinic receptor that direct phosphorylation/arrestin-dependent (non G-protein) signalling as being beneficial in cognitive disorders.

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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16


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