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The Journal of Neuroscience, September 28, 2005, 25(39):9027-9036; doi:10.1523/JNEUROSCI.2567-05.2005

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Cellular/Molecular
Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors

Rongsheng Jin,¹ Suzanne Clark,⁴ Autumn M. Weeks,⁴ Joshua T. Dudman,² Eric Gouaux,^1,3 and Kathryn M. Partin⁴

¹Department of Biochemistry and Molecular Biophysics, ²Center for Neurobiology and Behavior, and ³Howard Hughes Medical Institute, Columbia University, New York, New York 10032, and ⁴Department of Biomedical Sciences, Division of Neuroscience, Colorado State University, Fort Collins, Colorado 80523

Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer's disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1,3-oxazino benzo-1,4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the "hinge" in the ligand-binding core "clamshell" that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.

Key words: glutamate receptor; desensitization; deactivation; kinetics; crystallography; cyclothiazide; aniracetam; CX614

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Received June 22, 2005; revised August 12, 2005; accepted August 16, 2005.

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