Structure of an agonist-bound ionotropic glutamate receptor

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Science  29 Aug 2014:
Vol. 345, Issue 6200, pp. 1070-1074
DOI: 10.1126/science.1256508

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Activating a receptor to excite a neuron

Transmitting signals between nerve cells, occuring at structures known as synapses, is critical to processes such as learning and memory. Fast transmission occurs when glutamate is released from a presynaptic neuron and binds to ionotropic glutamate receptors (iGluRs) in the cell membrane of a postsynaptic neuron. The iGluR contains an ion channel that is transiently opened, to activate the postsynaptic neuron, but then closes rapidly. Chen et al. and Yelshanskaya et al. report crystal structures in a range of conformations that together provide insight into how glutamate binding causes the channel to open and how other molecules that bind to the receptor modulate this. The information could aid in the design of drugs to treat cognitive impairment or seizure disorders

Science, this issue p. 1021 and p. 1070


Ionotropic glutamate receptors (iGluRs) mediate most excitatory neurotransmission in the central nervous system and function by opening their ion channel in response to binding of agonist glutamate. Here, we report a structure of a homotetrameric rat GluA2 receptor in complex with partial agonist (S)-5-nitrowillardiine. Comparison of this structure with the closed-state structure in complex with competitive antagonist ZK 200775 suggests conformational changes that occur during iGluR gating. Guided by the structures, we engineered disulfide cross-links to probe domain interactions that are important for iGluR gating events. The combination of structural information, kinetic modeling, and biochemical and electrophysiological experiments provides insight into the mechanism of iGluR gating.

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