Reelin modulates NMDA receptor activity in cortical neurons.
Reelin, a large protein that regulates neuronal migration during embryonic development, activates a conserved signaling pathway that requires its receptors, very low-density lipoprotein receptor and apolipoprotein E receptor 2, the cytoplasmic adaptor protein Disabled-1 (Dab1), and Src family kinases (SFK). Reelin also markedly enhances long-term potentiation in the adult hippocampus, suggesting that this developmental signaling pathway can physiologically modulate learning and behavior. Here, we show that Reelin can regulate NMDA-type glutamate receptor activity through a mechanism that requires SFKs and Dab1. Reelin mediates tyrosine phosphorylation of and potentiates calcium influx through NMDA receptors in primary wild-type cortical neurons but not in Dab1 knock-out neurons or in cells in which Reelin binding to its receptors is blocked by a receptor antagonist. Inhibition of SFK abolishes Reelin-induced and glutamate-dependent enhancement of calcium influx. We also show that Reelin-induced augmentation of Ca2+ entry through NMDA receptors increases phosphorylation and nuclear translocation of the transcription factor cAMP-response element binding protein. Thus, Reelin may physiologically modulate learning and memory by modulating NMDA receptor functions.
Chen
Ying
Y
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Beffert
Uwe
U
Ertunc
Mert
M
Tang
Tie-Shan
TS
Kavalali
Ege T
ET
Bezprozvanny
Ilya
I
Herz
Joachim
J
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005260:Female; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D015816:Cell Adhesion Molecules, Neuronal; D018691:Excitatory Amino Acid Antagonists; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; C000717129:Reln protein, rat; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases