Desensitizing interactions The strength of synaptic responses is contr
Gouaux/MacmillanAMPA-sensitive glutamate receptors can either be activated or desensitized upon glutamate binding. Desensitization, in which the receptor is bound to ligand but inactive, allows for rapid cessation of signaling in the presence of agonist. AMPA receptors are arranged as heterotetramers, but Gouaux's group has determined that the functionally relevant structure for the ligand-binding core for desensitization is that of dimers of dimers.
Using crystallographic and functional analyses of site-directed mutant subunits of GluR2, they show that the stability of the dimer interface at the ligand-binding core correlates linearly with the extent of receptor desensitization. Mutations that strengthen this interaction are more resistant to desensitization, whereas disruption of dimerization promotes desensitization.
Dimer interaction takes place between domain 1 of the ligand-binding core in each subunit. When these interactions are strong, conformational changes induced by glutamate binding are more likely to take place by movement of domain 2. This movement forces open the channel of the receptor. Weaker dimer interactions make it more likely that domain 1 will move upon glutamate binding, breaking the dimer interface. When that happens, the channel is left closed, and although the receptor is bound, Na ions cannot pass.
These studies also explain the mode of action of a drug that promotes AMPA activation, cyclothiazide (CTZ). CTZ binding in the ligand-binding core of the receptor stabilizes the dimer interface, thus reducing receptor sensitivity to desensitization.
Reference:
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