Modulation of the channel activity of the ε2/ζ1-subtype N-methyl D- aspartate receptor by PSD-95

Abstract

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 ε subunit of the receptors. The effects of PSD-95 on the channel activity of the ε2/ζ1 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 ε2 subunit of the NMDA receptor and the second PSD95/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 MDA 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 ε2/ζ1 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.