Title : The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation\/arrestin-dependent manner - Poulin_2010_Proc.Natl.Acad.Sci.U.S.A_107_9440 |
Author(s) : Poulin B , Butcher A , McWilliams P , Bourgognon JM , Pawlak R , Kong KC , Bottrill A , Mistry S , Wess J , Rosethorne EM , Charlton SJ , Tobin AB |
Ref : Proc Natl Acad Sci U S A , 107 :9440 , 2010 |
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. |
PubMedSearch : Poulin_2010_Proc.Natl.Acad.Sci.U.S.A_107_9440 |
PubMedID: 20439723 |
Poulin B, Butcher A, McWilliams P, Bourgognon JM, Pawlak R, Kong KC, Bottrill A, Mistry S, Wess J, Rosethorne EM, Charlton SJ, Tobin AB (2010)
The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation\/arrestin-dependent manner
Proc Natl Acad Sci U S A
107 :9440
Poulin B, Butcher A, McWilliams P, Bourgognon JM, Pawlak R, Kong KC, Bottrill A, Mistry S, Wess J, Rosethorne EM, Charlton SJ, Tobin AB (2010)
Proc Natl Acad Sci U S A
107 :9440