N-methyl-D-aspartate receptors mediate the phosphorylation and desensitization of muscarinic receptors in cerebellar granule neurons

Adrian J Butcher; Ignacio Torrecilla; Kenneth W Young; Kok Choi Kong; Sharad C Mistry; Andrew R Bottrill; Andrew B Tobin

doi:10.1074/jbc.M901031200

N-methyl-D-aspartate receptors mediate the phosphorylation and desensitization of muscarinic receptors in cerebellar granule neurons

J Biol Chem. 2009 Jun 19;284(25):17147-17156. doi: 10.1074/jbc.M901031200. Epub 2009 Mar 30.

Authors

Adrian J Butcher¹, Ignacio Torrecilla¹, Kenneth W Young², Kok Choi Kong¹, Sharad C Mistry³, Andrew R Bottrill³, Andrew B Tobin⁴

Affiliations

¹ From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
² Medical Research Council Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
³ Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom.
⁴ From the Department of Cell Physiology and Pharmacology, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, United Kingdom. Electronic address: tba@le.ac.uk.

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

Grants and funding

047600/Wellcome Trust/United Kingdom