title: N-methyl-D-aspartate receptors mediate the phosphorylation and desensitization of muscarinic receptors in cerebellar granule neurons.
abstract: Changes in synaptic strength mediated by ionotropic glutamate N-methyl-D-asparate (NMDA) receptors is generally considered to be the molecular mechanism underlying memory and learning. NMDA receptors themselves are subject to regulation through signaling pathways that are activated by G-protein-coupled receptors (GPCRs). In this study we investigate the ability of NMDA receptors to regulate the signaling of GPCRs by focusing on the G(q/11)-coupled M(3)-muscarinic receptor expressed endogenously in mouse cerebellar granule neurons. We show that NMDA receptor activation results in the phosphorylation and desensitization of M(3)-muscarinic receptors through a mechanism dependent on NMDA-mediated calcium influx and the activity of calcium-calmodulin-dependent protein kinase II. Our study reveals a complex pattern of regulation where GPCRs (M(3)-muscarinic) and NMDA receptors can feedback on each other in a process that is likely to influence the threshold value of signaling networks involved in synaptic plasticity.
authors.affiliation: From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Butcher
authors.affiliation: From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Torrecilla
authors.affiliation: Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Young
authors.affiliation: From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Kok Choi
authors.initials: KC
authors.lastname: Kong
authors.affiliation: Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Sharad C
authors.initials: SC
authors.lastname: Mistry
authors.affiliation: Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Bottrill
authors.affiliation: From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom. Electronic address: tba@le.ac.uk.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Tobin