Modulation of the channel activity of the epsilon 2/zeta 1-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 o f the epsilon subunit of the receptors. The effects of PSD-95 on the channe l activity of the epsilon 2/zeta 1 heteromeric NMDA receptor were examined by injection of PSD-95 cRNA into Xenopus oocytes expressing the NMDA recept ors. Expression of PSD-95 decreased the sensitivity of the NMDA receptor ch annels to L-glutamate. Mutational studies showed that the interaction betwe en the COOH terminus of the epsilon 2 subunit of the NMDA receptor and the second PSD-95/Dlg/Z0-1 domain of PSD-95 is critical for the decrease in glu tamate sensitivity. It is known that protein kinase C markedly potentiates the channel activity of the MMDA receptor expressed in oocytes. PSD-95 inhi bited the protein kinase C-mediated potentiation of the channels. Thus, we demonstrated that PSD-95 functionally modulates the channel activity of the epsilon 2/zeta 1 NMDA receptor. PSD-95 makes signal transmission more effi cient 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.