The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1.
The NMDA subtype of glutamate receptors (NMDAR) at excitatory neuronal synapses plays a key role in synaptic plasticity. The extracellular signal-regulated kinase (ERK1,2 or ERK) pathway is an essential component of NMDAR signal transduction controlling the neuroplasticity underlying memory processes, neuronal development, and refinement of synaptic connections. Here we show that NR2B, but not NR2A or NR1 subunits of the NMDAR, interacts in vivo and in vitro with RasGRF1, a Ca(2+)/calmodulin-dependent Ras-guanine-nucleotide-releasing factor. Specific disruption of this interaction in living neurons abrogates NMDAR-dependent ERK activation. Thus, RasGRF1 serves as NMDAR-dependent regulator of the ERK kinase pathway. The specific association of RasGRF1 with the NR2B subunit and study of ERK activation in neurons with varied content of NR2B suggests that NR2B-containing channels are the dominant activators of the NMDA-dependent ERK pathway.
Krapivinsky
Grigory
G
Howard Hughes Medical Institute, Children's Hospital, 1309 Enders Building, 320 Longwood Avenue, Boston, MA 02115, USA.
Krapivinsky
Luba
L
Manasian
Yunona
Y
Ivanov
Anton
A
Tyzio
Roman
R
Pellegrino
Christophe
C
Ben-Ari
Yehezkel
Y
Clapham
David E
DE
Medina
Igor
I
D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005333:Fetus; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000235:genetics; D009924:Organ Culture Techniques; D010455:Peptides / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D013569:Synapses / Q000201:enzymology*; D009435:Synaptic Transmission / Q000235:genetics; D020666:ras-GRF1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C121001:NR2B NMDA receptor; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D020666:ras-GRF1; D016202:N-Methylaspartate; D020928:Mitogen-Activated Protein Kinases