NMDA receptor-dependent synaptic translocation of insulin receptor substrate p53 via protein kinase C signaling.
The activity-dependent remodeling of postsynaptic structure is a fundamental process underlying learning and memory. Insulin receptor substrate p53 (IRSp53), a key player in cytoskeletal dynamics, is enriched in the postsynaptic density (PSD) fraction, but its significance in synaptic functions remains unclear. We report here that IRSp53 is accumulated rapidly at the postsynaptic sites of cultured hippocampal neurons after glutamate or NMDA stimulation in an actin cytoskeleton-dependent manner. Pharmacological profiles showed that a PKC inhibitor, but not other kinase inhibitors, specifically suppressed the synaptic translocation of IRSp53 in response to NMDA, and the selective activation of PKC with phorbol ester markedly induced the synaptic translocation. Reverse transcriptase-PCR and Western blotting showed that IRSp53-S is the major isoform expressed in cultured hippocampal neurons. The synaptic targeting of IRSp53-S was found to be mediated through N-terminal coiled-coil domain and the PDZ (PSD-95/Discs large/zona occludens-1)-binding sequence at its C-terminal end and regulated by the PKC phosphorylation of its N terminus. In electrophysiological experiments, overexpression of IRSp53-S wild type and IRSp53-S mutant that is spontaneously accumulated at the postsynaptic sites enhanced the postsynaptic function as detected by an increased miniature EPSC amplitude. These data suggest that IRSp53 is involved in NMDA receptor-linked synaptic plasticity via PKC signaling.
Hori
Kei
K
Department of Neuroscience (D13) and Division of Neurophysiology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Yasuda
Hiroki
H
Konno
Daijiro
D
Maruoka
Hisato
H
Tsumoto
Tadaharu
T
Sobue
Kenji
K
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
C119539:BAIAP2 protein, human; D007328:Insulin; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D011493:Protein Kinase C