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Glutamate is the major excitatory neurotransmitter in the mammalian brain. The
(S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole)propionic acid (AMPA)-subtype
glutamate receptor, a ligand-gated ion channel, mediates most of the fast
excitatory synaptic transmission in the mammalian central nervous system. Here
we present electrophysiological, biochemical, and crystallographic data on the
interactions between quisqualate and the GluR2 receptor ion channel and its
corresponding ligand binding core. Quisqualate is a high-affinity, full agonist
which like AMPA and glutamate elicits maximum peak current responses, and
stabilizes the ligand binding core in a fully closed conformation, reinforcing
the concept that full agonists produce similar conformational changes
[Armstrong, N., and Gouaux, E. (2000) Neuron 28, 165-181]. Nevertheless, the
mechanism of quisqualate binding is different from that of AMPA but similar to
that of glutamate, illustrating that quisqualate is a faithful glutamate
analogue. A detailed comparison of the three agonist complexes reveals distinct
binding mechanisms, particularly in the region of a hydrophobic pocket that is
proximal to the anionic gamma-substituents, and demonstrates the importance of
agonist-water-receptor interactions. The hydrophobic pocket, which is predicted
to vary in chemical character between receptor subtypes, probably plays an
important role in determining receptor subtype specificity.
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