Modulation of the channel activity of the epsilon2/zeta1-subtype N-methyl D-aspartate receptor by PSD-95.
A channel-associated protein PSD-95 has been shown to induce clustering of N-methyl D-aspartate (NMDA) receptors, interacting with the COOH terminus of the epsilon subunit of the receptors. The effects of PSD-95 on the channel activity of the epsilon2/zeta1 heteromeric NMDA receptor were examined by injection of PSD-95 cRNA into Xenopus oocytes expressing the NMDA receptors. Expression of PSD-95 decreased the sensitivity of the NMDA receptor channels to L-glutamate. Mutational studies showed that the interaction between the COOH terminus of the epsilon2 subunit of the NMDA receptor and the second PSD-95/Dlg/Z0-1 domain of PSD-95 is critical for the decrease in glutamate sensitivity. It is known that protein kinase C markedly potentiates the channel activity of the NMDA receptor expressed in oocytes. PSD-95 inhibited the protein kinase C-mediated potentiation of the channels. Thus, we demonstrated that PSD-95 functionally modulates the channel activity of the epsilon2/zeta1 NMDA receptor. PSD-95 makes signal transmission more efficient by clustering the channels at postsynaptic sites. In addition to this, our results suggest that PSD-95 plays a protective role against neuronal excitotoxicity by decreasing the glutamate sensitivity of the channels and by inhibiting the protein kinase C-mediated potentiation of the channels.
Department of Pharmacology, Yamaguchi University School of Medicine, 1144 Kogushi, Ube, Yamaguchi 755-8505, Japan.
Y
Y
Yamada
Y
Y
Chochi
K
K
Takamiya
K
K
Sobue
M
M
Inui
D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D004594:Electrophysiology; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D015640:Ion Channel Gating / Q000235:genetics*; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018075:RNA, Complementary / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014981:Xenopus
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018075:RNA, Complementary; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D051528:Guanylate Kinases