Molecular Biological Studies on the Excitatory Synaptic Transmission in the Central Nervous System

The NMDA receptor channel plays a key role in activity-dependent synaptic plasticity such as long-term potentiation, which is thought to underlie memory and learning, and in experience-dependent synaptic plasticity of the developing brain. Abnormal activation of the NMDA receptor channel may trigger the neuronal cell death observed in various brain disorders. We have identified more than a dozen subunits of the glutamate receptor channel by molecular cloning. These subunits have been classified into six subfamilies according to the amino acid sequence homology. The members of the α subfamily constitute the AMPA-selective glutamate receptor channel, whereas the β and γ subfamilies include the subunits of the kainate-selective glutamate receptor channel. Highly active NMDA receptor channels are formed only when the distantly related ε snd ζ subunits are expressed together. The members of the ε subfamily are distinct with each other in function, distribution and regulation. In contrast to the wide distribution of the ε1 and ζ1 subunit mRNAs in the brain, the ε2 subunit mRNA is expressed selectively in the forebrain, and the ε3 subunit mRNA is found predominantly in the cerebellum. Functional analyses of the ε/ζ heteromeric NMDA receptor channels expressed from cloned cDNAs provide evidence that the molecular diversity of the ε subfamily underlies the functional heterogeneity of the NMDA receptor channel. Furthermore, we have identified a Mg＾<2+> block site of the NMDA receptor channel by site-directed mutagenesis