N-methyl-D-aspartate receptors mediate the phosphorylation and desensitization of muscarinic receptors in cerebellar granule neurons.
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.
Butcher
Adrian J
AJ
From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
Torrecilla
Ignacio
I
From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
Young
Kenneth W
KW
Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
Kong
Kok Choi
KC
From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
Mistry
Sharad C
SC
Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
Bottrill
Andrew R
AR
Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
Tobin
Andrew B
AB
From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom. Electronic address: tba@le.ac.uk.