title: The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner.
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 M(1)-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 M(3)-muscarinic receptor that is expressed in numerous brain regions including the hippocampus. We demonstrate here that M(3)-muscarinic receptor knockout mice show a deficit in fear conditioning learning and memory. The mechanism used by the M(3)-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 M(3)-muscarinic receptor is phosphorylated in the hippocampus following agonist treatment and following fear conditioning training. Importantly, the phosphorylation-deficient M(3)-muscarinic receptor was coupled normally to G(q/11)-signaling but was uncoupled from phosphorylation-dependent processes such as receptor internalization and arrestin recruitment. It can, therefore, be concluded that M(3)-muscarinic receptor-dependent learning and memory depends, at least in part, on receptor phosphorylation/arrestin signaling. This study opens the potential for biased M(3)-muscarinic receptor ligands that direct phosphorylation/arrestin-dependent (non-G protein) signaling as being beneficial in cognitive disorders.
authors.affiliation: Department of Cell Physiology and Pharmacology and Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Benoit
authors.initials: B
authors.lastname: Poulin
authors.forename: Adrian
authors.initials: A
authors.lastname: Butcher
authors.forename: Phillip
authors.initials: P
authors.lastname: McWilliams
authors.forename: Julie-Myrtille
authors.initials: JM
authors.lastname: Bourgognon
authors.forename: Robert
authors.initials: R
authors.lastname: Pawlak
authors.forename: Kok Choi
authors.initials: KC
authors.lastname: Kong
authors.forename: Andrew
authors.initials: A
authors.lastname: Bottrill
authors.forename: Sharad
authors.initials: S
authors.lastname: Mistry
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Rosethorne
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Tobin
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D019393:Arrestin / Q000378:metabolism; D003213:Conditioning, Psychological; D005239:Fear; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007858:Learning / Q000502:physiology*; D013058:Mass Spectrometry; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D019393:Arrestin; D043587:Receptor, Muscarinic M3; D043802:GTP-Binding Protein alpha Subunits, Gq-G11