Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors.
Protein-protein interactions and calcium entry through the N-methyl-d-aspartate (NMDA)-type glutamate receptor regulate synaptic development and plasticity in the central nervous system. The EphB receptor tyrosine kinases are localized at excitatory synapses where they cluster and associate with NMDA receptors. We identified a mechanism whereby EphBs modulate NMDA receptor function. EphrinB2 activation of EphB in primary cortical neurons potentiates NMDA receptor-dependent influx of calcium. Treatment of cells with ephrinB2 led to NMDA receptor tyrosine phosphorylation through activation of the Src family of tyrosine kinases. These ephrinB2-dependent events result in enhanced NMDA receptor-dependent gene expression. Our findings indicate that ephrinB2 stimulation of EphB modulates the functional consequences of NMDA receptor activation and suggest a mechanism whereby activity-independent and activity-dependent signals converge to regulate the development and remodeling of synaptic connections.
Takasu
Mari A
MA
Division of Neuroscience, Children's Hospital, and the Department of Neurobiology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Dalva
Matthew B
MB
Zigmond
Richard E
RE
Greenberg
Michael E
ME
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D036388:Ephrin-B2; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments; D008565:Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D008959:Models, Neurological; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D036224:Receptor, EphB4; D036081:Receptors, Eph Family; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism; D014158:Transcription, Genetic; D019061:src-Family Kinases / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D036388:Ephrin-B2; D007141:Immunoglobulin Fc Fragments; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D011518:Proto-Oncogene Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D019000:Phosphotyrosine; D018698:Glutamic Acid; D020794:Receptor Protein-Tyrosine Kinases; D036224:Receptor, EphB4; D036081:Receptors, Eph Family; C494957:FYN protein, human; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; D002118:Calcium