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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Calcium Signaling
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
-
Cells, Cultured
-
Cerebellum / cytology
-
Cerebellum / metabolism*
-
Feedback, Physiological
-
Mice
-
Mice, Knockout
-
Molecular Sequence Data
-
N-Methylaspartate / pharmacology
-
Neuronal Plasticity
-
Neurons / drug effects
-
Neurons / metabolism
-
Phosphatidylinositols / metabolism
-
Phosphorylation
-
Receptor, Muscarinic M3 / chemistry
-
Receptor, Muscarinic M3 / deficiency
-
Receptor, Muscarinic M3 / genetics
-
Receptor, Muscarinic M3 / metabolism*
-
Receptors, N-Methyl-D-Aspartate / metabolism*
-
Recombinant Fusion Proteins / chemistry
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / metabolism
-
Signal Transduction
Substances
-
Phosphatidylinositols
-
Receptor, Muscarinic M3
-
Receptors, N-Methyl-D-Aspartate
-
Recombinant Fusion Proteins
-
N-Methylaspartate
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2