Stargazin Modulation of AMPA Receptors

Shaikh, Sana; Dolino, Drew M.; Lee, Garam; Chatterjee, Sudeshna; MacLean, David M.; Flatebo, Charlotte; Landes, Christy F.; Jayaraman, Vasanthi

doi:10.1016/j.celrep.2016.09.014

Cited by 52 publications

(59 citation statements)

References 38 publications

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“…The ATD tetramer moves nearly as a rigid body, translating 5 Å downward and rotating by 18° (Figure 6). Consistent with recent functional, mutagenesis, LRET and smFRET experiments (Shaikh et al, 2016; Yelshanskaya et al, 2016a), the ATD interdimer interface remains largely intact (Figure S6D), with the cross-dimer distance between G212 Cα′s staying approximately the same in GluA2-2xGSG1L ZK (5.9 Å) as in GluA2-2xGSG1L Quis (5.6 Å), and the dimers rotating away from each other only slightly (by ~4° cumulatively). For both GluA2-2xGSG1L ZK and GluA2-2xGSG1L Quis , we did not observe separation of ATD dimers in our 3D classification at any stage in the image processing (Figure S2).…”

Section: Resultssupporting

confidence: 86%

Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes

Twomey

Yelshanskaya

Grassucci

et al. 2017

Neuron

100

161

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SUMMARY Fast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits that modulate AMPAR assembly, trafficking, gating and pharmacology. Aberrancies in AMPAR-mediated signaling are associated with numerous neurological disorders. Here, we report cryo-EM structures of an AMPAR in complex with the auxiliary subunit GSG1L in the closed and desensitized states. GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by profound structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local two-fold rotational symmetry. Our structural and functional experiments suggest that AMPAR auxiliary subunits share a modular architecture and use a common transmembrane scaffold for distinct extracellular modules to differentially regulate AMPAR gating. By comparing the AMPAR-GSG1L complex structures, we map conformational changes accompanying AMPAR recovery from desensitization and reveal structural bases for regulation of synaptic transmission by auxiliary subunits.

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Section: Resultssupporting

confidence: 86%

Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes

Twomey

Yelshanskaya

Grassucci

et al. 2017

Neuron

100

161

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“…To recover from desensitization back to the resting state, the ATD must then rotate counter-clockwise by 18˚. Maintenance of the ATD tetrameric arrangement in different gating states 29,40 emphasizes importance of the ATDs for iGluR assembly 41–45 , while enormous rigid body rotations provide a way to fine tune synaptic transmission via altering cross-synaptic interactions 46 .…”

Section: Gating Mechanismmentioning

confidence: 99%

Channel opening and gating mechanism in AMPA-subtype glutamate receptors

Twomey

Yelshanskaya

Grassucci

et al. 2017

Nature

200

345

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Summary AMPA-subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission throughout the central nervous system. Gated by the neurotransmitter glutamate, AMPA receptors are critical for synaptic strength and dysregulation of AMPA receptor-mediated signaling is linked to numerous neurological diseases. Here, we use cryo-electron microscopy to solve the structures of AMPA receptor-auxiliary subunit complexes in the apo, antagonist and agonist-bound states and elucidate the iris-like mechanism of ion channel opening. The ion channel selectivity filter is formed by the extended portions of the re-entrant M2 loops, while the helical portions of M2 contribute to extensive hydrophobic interfaces between AMPA receptor subunits in the ion channel. We show how the permeation pathway changes upon channel opening and identify conformational changes throughout the entire AMPA receptor that accompany activation and desensitization. Our findings provide a framework for understanding gating across the family of ionotropic glutamate receptors and the role of AMPA receptors in excitatory neurotransmission.

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“…A number of investigations have focused on the structure and mechanism of modulation of AMPA receptors with the TARP stargazin, also known as γ2 (Cho et al, 2007;Tomita et al, 2005;MacLean and Bowie, 2011;MacLean et al, 2014;Cais et al, 2014;Zhang et al, 2014;Carbone and Plested, 2016;Shaikh et al, 2016;Twomey et al, 2016;Zhao et al, 2016;Coombs et al, 2017;Ben-Yaacov et al, 2017;Twomey et al, 2017;Baranovic and Plested, 2018). These studies show that γ2 interacts with the lower lobe of the ligand-binding domain (LBD) and the preM1 linker via an electrostatic patch, which may stabilize closed cleft states of the LBD, enhancing agonist efficacy.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of modulation of AMPA receptors by TARP-γ8

Carrillo

Shaikh

Berka

et al. 2019

Journal of General Physiology

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Fast excitatory synaptic transmission in the mammalian central nervous system is mediated by glutamate-activated α-amino-5-methyl-3-hydroxy-4-isoxazole propionate (AMPA) receptors. In neurons, AMPA receptors coassemble with transmembrane AMPA receptor regulatory proteins (TARPs). Assembly with TARP γ8 alters the biophysical properties of the receptor, producing resensitization currents in the continued presence of glutamate. Using single-channel recordings, we show that under resensitizing conditions, GluA2 AMPA receptors primarily transition to higher conductance levels, similar to activation of the receptors in the presence of cyclothiazide, which stabilizes the open state. To study the conformation associated with these states, we have used single-molecule FRET and show that this high-conductance state exhibits tighter coupling between subunits in the extracellular parts of the receptor. Furthermore, the dwell times for the transition from the tightly coupled state to the decoupled states correlate to longer open durations of the channels, thus correlating conformation and function at the single-molecule level.

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Stargazin Modulation of AMPA Receptors

Cited by 52 publications

References 38 publications

Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes

Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes

Channel opening and gating mechanism in AMPA-subtype glutamate receptors

Mechanism of modulation of AMPA receptors by TARP-γ8

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