The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner |
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Authors: | Benoit Poulin Adrian Butcher Phillip McWilliams Julie-Myrtille Bourgognon Robert Pawlak Kok Choi Kong Andrew Bottrill Sharad Mistry Jürgen Wess Elizabeth M. Rosethorne Steven J. Charlton Andrew B. Tobin |
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Affiliation: | aDepartment of Cell Physiology and Pharmacology and;bProtein and Nucleic Acid Chemistry Laboratory, University of Leicester, Leicester LE1 9HN, United Kingdom;;cMolecular Signaling Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810; and;dNovartis Institutes for Biomedical Research, Sussex RH125AB, United Kingdom |
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Abstract: | 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 signaling through the cholinergic M1-muscarinic receptor subtype. However, recent studies have cast doubt on whether this is the primary receptor mediating cholinergic-hippocampal learning and memory. The current study offers an alternative mechanism involving the M3-muscarinic receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M3-muscarinic receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M3-muscarinic receptor in this process involves receptor phosphorylation because a knockin mouse strain expressing a phosphorylation-deficient receptor mutant also shows a deficit in 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-signaling but was uncoupled from phosphorylation-dependent processes such as receptor internalization and arrestin recruitment. It can, therefore, be concluded that M3-muscarinic receptor–dependent learning and memory depends, at least in part, on receptor phosphorylation/arrestin signaling. This study opens the potential for biased M3-muscarinic receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders. |
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Keywords: | fear conditioning G protein-coupled receptor hippocampus ligand bias Alzheimer''s disease |
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