A novel Ca2+-independent signaling pathway to extracellular signal-regulated protein kinase by coactivation of NMDA receptors and metabotropic glutamate receptor 5 in neurons.
The specification and organization of glutamatergic synaptic transmission require the coordinated interaction among glutamate receptors and their synaptic adaptor proteins closely assembled in the postsynaptic density (PSD). Here we investigated the interaction between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5) in the integral regulation of extracellular signal-regulated protein kinase (ERK) and gene expression in cultured rat striatal neurons. We found that coapplication of NMDA and the mGluR5 agonist (S)-3,5-dihydroxyphenylglycine synergistically increased ERK phosphorylation. Interestingly, the synergistic increase in ERK phosphorylation was dependent on the cross talk between NMDA receptor-associated synaptic adaptor protein PSD-95 and the mGluR5-linked adaptor protein Homer1b/c but not on the conventional Ca2+ signaling derived from NMDA receptors (Ca2+ influx) and mGluR5 (intracellular Ca2+ release). This was demonstrated by the findings that the synergistic phosphorylation of ERK induced by coactivation of NMDA receptors and mGluR5 was blocked by either a Tat peptide that disrupts NMDA receptor/PSD-95 binding or small interfering RNAs that selectively reduce cellular levels of Homer1b/c. Furthermore, ERK activated through this PSD-95/Homer1b/c-dependent and Ca2+-independent pathway was able to phosphorylate the two key transcription factors Elk-1 and cAMP response element-binding protein, which further leads to facilitation of c-Fos expression. Together, we have identified a novel Ca2+-independent signaling pathway to ERK by the synergistic interaction of NMDA receptors and mGluR5 via their adaptor proteins in the PSD of neurons, which underlies a synapse-to-nucleus communication important for the transcriptional regulation.
Yang
Lu
L
Department of Basic Medical Science, University of Missouri-Kansas City, School of Medicine, Kansas City, Missouri 64108, USA.
Mao
Limin
L
Tang
Qingsong
Q
Samdani
Shazia
S
Liu
Zhenguo
Z
Wang
John Q
JQ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002227:Carbazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology*; D002467:Cell Nucleus / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004075:Diglycerides / Q000502:physiology; D000076122:Disks Large Homolog 4 Protein; D004789:Enzyme Activation; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D000072233:Homer Scaffolding Proteins; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D017136:Ion Transport; D007527:Isoenzymes / Q000502:physiology; D008301:Maleimides; D008565:Membrane Proteins; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000201:enzymology / Q000502:physiology; D054799:Phospholipase C beta; D010766:Phosphorylation / Q000187:drug effects; D025941:Protein Interaction Mapping; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D010738:Type C Phospholipases / Q000502:physiology; D050807:ets-Domain Protein Elk-1
D002118:Calcium; D002227:Carbazoles; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004075:Diglycerides; D000076122:Disks Large Homolog 4 Protein; D018690:Excitatory Amino Acid Agonists; D000072233:Homer Scaffolding Proteins; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008301:Maleimides; D008565:Membrane Proteins; D008734:Methoxyhydroxyphenylglycol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016202:N-Methylaspartate; D009419:Nerve Tissue Proteins; D054799:Phospholipase C beta; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D012964:Sodium; D014157:Transcription Factors; D010738:Type C Phospholipases; D050807:ets-Domain Protein Elk-1; C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; C501449:Dlg4 protein, rat; C494114:Elk1 protein, rat; C121001:NR2B NMDA receptor; C033652:postsynaptic density proteins; C010117:3,4-dihydroxyphenylglycol; C064758:Ro 31-8220