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L-glutamate, the major excitatory neurotransmitter in the human brain, activates
a family of ligand-gated ion channels, the major subtypes of which are named
AMPA, kainate, and NMDA receptors. In common with many signal transduction
proteins, glutamate receptors are modulated by ions and small molecules,
including Ca(2+), Mg(2+), Zn(2+), protons, polyamines, and steroids. Strikingly,
the activation of kainate receptors by glutamate requires the presence of both
Na(+) and Cl(-) in the extracellular solution, and in the absence of these ions,
receptor activity is abolished. Here, we identify the site and mechanism of
action of anions. Surprisingly, we find that Cl(-) ions are essential structural
components of kainate receptors. Cl(-) ions bind in a cavity formed at the
interface between subunits in a dimer pair. In the absence of Cl(-), dimer
stability is reduced, the rate of desensitization increases, and the fraction of
receptors competent for activation by glutamate drops precipitously.
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