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 GluRdelta2 (A654T) glutamate receptor subunit converts it into a functional channel, and a spontaneous mutation at this site is thought to be responsible for the neurodegeneration of neurons in the Lurcher mouse. This mutation is located in a hydrophobic region of the M3 domain of this subunit, and this alanine is conserved throughout many of the glutamate receptors. We show here that site-directed mutagenesis of the homologous alanine (A636T; GluR1-L(c)) in the GluR1 AMPA receptor subunit alters its channel properties. The apparent potencies of both kainate and glutamate were increased 85- and 2000-fold, respectively. Furthermore, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)was converted from a competitive antagonist into a potent agonist. Our results demonstrate that a single amino acid within or near the putative second transmembrane region of the GluR1 subunit is critical for the binding/gating properties of this AMPA receptor.
Taverna
F
F
Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Xiong
Z G
ZG
Brandes
L
L
Roder
J C
JC
Salter
M W
MW
MacDonald
J F
JF
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D004553:Electric Conductivity; D005071:Evoked Potentials; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D007608:Kainic Acid / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D007473:Ion Channels; D007608:Kainic Acid; D018091:Receptors, AMPA