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2 Publications

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    09/28/05 | Mechanism of positive allosteric modulators acting on AMPA receptors.
    Jin R, Clark S, Weeks AM, Dudman JT, Gouaux E, Partin KM
    The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2005 Sep 28;25(39):9027-36. doi: 10.3389/fnana.2010.00147

    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.

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    05/01/05 | Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat.
    MacDonald ML, Eaton ME, Dudman JT, Konradi C
    Biological Psychiatry. 2005 May 1;57(9):1041-51. doi: 10.3389/fnana.2010.00147

    Molecular adaptations are believed to contribute to the mechanism of action of antipsychotic drugs (APDs). We attempted to establish common gene regulation patterns induced by chronic treatment with APDs.

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