Molecular biology of glutamate receptors

Abstract The ligand-gated receptors for L-glutamate play a central role in acute neuronal degeneration. Recently cDNAs have been isolated for subunits of several glutamate receptor subtypes. By sequence homology all these subunits clearly belong to one large gene family. Several subfamilies exist and match roughly previously pharmacologically and electrophysiologically defined subtypes of glutamate receptors. Currently four genes (GluR A, B, C and D) are known that code for the AMPA subtypes of glutamate receptors. Recombinant expression of wild type and mutated sequences identified a critical residue in the putative TM2 channel-lining segment that controls Ca 2+ ion permeability. The arginine (R) found in GluR B subunits at that position renders AMPA channels impermeable for Ca 2+ ions, whereas glutamine (Q) containing GluR A, C and D subunits give rise to Ca 2+ permeable channels. RNA editing converts the genomically encoded glutamine codon into the arginine condon found in GluR B cDNAs for the Q/R site. NMDA subtypes of glutamate receptors are formed after coexpression of the NR1 cDNA with a cDNA of the NR2 family. Depending on the member of the NR2 family used, NMDA receptors with different kinetical and pharmacological properties are generated. Common to all channels of these NMDA receptors is a high permeability for Ca 2+ ions and a voltage dependent block by Mg 2+ ions. All currently known NMDA receptor subunits have an asparagine at the Q/R homologous position. We found that this residue is critical for Mg 2+ block and Ca 2+ permeability of NMDA receptor channels.