The Lurcher mutation of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit enhances potency of glutamate and converts an antagonist to an agonist

A point mutation of the GluR delta 2 (A654T) glutamate receptor subunit con verts it into a functional channel, and a spontaneous mutation at this site is thought to be responsible for the neurodegeneration of neurons in the L urcher mouse. This mutation is located in a hydrophobic region of the M3 do main of this subunit, and this alanine is conserved throughout many of the glutamate receptors. We show here that site-directed mutagenesis of the hom ologous alanine (A636T; GluR1-L-c) in the GluR1 AMPA receptor subunit alter s its channel properties. The apparent potencies of both kainate and glutam ate were increased 85- and 2000-fold, respectively. Furthermore, 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX)was converted from a competitive antagonis t into a potent agonist, Our results demonstrate that a single amino acid w ithin or near the putative second transmembrane region of the GluR1 subunit is critical for the binding/gating properties of this AMPA receptor.