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Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy

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Science  01 Jul 2016:
Vol. 353, Issue 6294, pp. 83-86
DOI: 10.1126/science.aaf8411

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Stargazin and the AMPA receptor

AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and contribute to higher cognitive processes such as learning and memory. In the brain, AMPARs exist as protein-protein complexes with various auxiliary subunits that tightly control AMPAR trafficking, gating, and pharmacology. Disruption of these complexes is implicated in numerous psychiatric and neurodegenerative diseases. Twomey et al. used cryo-electron microscopy to solve the structure of an AMPAR complex with stargazin (STZ), the major representative of transmembrane AMPAR regulatory proteins. STZ controls AMPAR synaptic targeting, synaptic plasticity, compartment-specific activity, pharmacology, and gating.

Science, this issue p. 83

Abstract

AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and contribute to high cognitive processes such as learning and memory. In the brain, AMPAR trafficking, gating, and pharmacology is tightly controlled by transmembrane AMPAR regulatory proteins (TARPs). Here, we used cryo–electron microscopy to elucidate the structural basis of AMPAR regulation by one of these auxiliary proteins, TARP γ2, or stargazin (STZ). Our structures illuminate the variable interaction stoichiometry of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR. Analysis of the AMPAR-STZ binding interfaces suggests that electrostatic interactions between the extracellular domains of AMPAR and STZ play an important role in modulating AMPAR function through contact surfaces that are conserved across AMPARs and TARPs. We propose a model explaining how TARPs stabilize the activated state of AMPARs and how the interactions between AMPARs and their auxiliary proteins control fast excitatory synaptic transmission.

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