The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Gan, Quan; Dai, Jixun; Zhou, Huan‐Xiang; Wollmuth, Lonnie P.

doi:10.1074/jbc.m115.686246

Cited by 24 publications

(49 citation statements)

References 55 publications

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“…Thus, minor overall movements in the GluK4-GluK4 dimer model compared with the GluK1-GluK1 dimer seem to be necessary in order to avoid steric clash. This would be consistent with the previous suggestion that the N-terminal domain of GluK5 plays an important role in receptor assembly (Kumar and Mayer, 2010) and that the transmembrane domain mediates tetramerization of AMPA receptors with other domains playing modulatory roles (Gan et al, 2016). However, direct evidence must await a full-length heteromeric structure consisting of low-affinity and high-affinity kainate receptor subunits.…”

Section: Gluk4 Dimer Interfacesupporting

confidence: 90%

The Structure of a High-Affinity Kainate Receptor: GluK4 Ligand-Binding Domain Crystallized with Kainate

Kristensen

Møllerud

et al. 2016

Structure

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Ionotropic glutamate receptors play a key role in fast neurotransmission in the CNS and have been linked to several neurological diseases and disorders. One subfamily is the kainate receptors, which are grouped into low-affinity (GluK1-3) and high-affinity (GluK4-5) receptors based on their affinity for kainate. Although structures of the ligand-binding domain (LBD) of all low-affinity kainate receptors have been reported, no structures of the high-affinity receptor subunits are available. Here, we present the X-ray structure of GluK4-LBD with kainate at 2.05 Å resolution, together with thermofluor and radiolabel binding affinity data. Whereas binding-site residues in GluK4 are most similar to the AMPA receptor subfamily, the domain closure and D1-D2 interlobe contacts induced by kainate are similar to the low-affinity kainate receptor GluK1. These observations provide a likely explanation for the high binding affinity of kainate at GluK4-LBD.

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Section: Gluk4 Dimer Interfacesupporting

confidence: 90%

The Structure of a High-Affinity Kainate Receptor: GluK4 Ligand-Binding Domain Crystallized with Kainate

Kristensen

Møllerud

et al. 2016

Structure

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“…; Gan et al . ). We then asked if the mutants (N63S and N363S) form functional tetramers, and BN‐PAGE analysis demonstrated that glycosylation mutants (N63S and N363S) were unable to form tetramers and accumulated at higher sizes (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…It is well accepted that glutamate receptors form tetrameric subunits complexes (Mano and Teichberg 1998). WT GluA1 AMPA-Rs were detected on BN-PAGE predominantly as tetramers and, weakly, as monomers and dimers in neurons and HEK 293 cells (Greger et al 2002(Greger et al , 2003(Greger et al , 2006Vandenberghe et al 2005;Gan et al 2016). We then asked if the mutants (N63S and N363S) form functional tetramers, and BN-PAGE analysis demonstrated that glycosylation mutants (N63S and N363S) were unable to form tetramers and accumulated at higher sizes (Fig.…”

Section: Resultsmentioning

confidence: 98%

N‐glycosylation of the AMPA‐type glutamate receptor regulates cell surface expression and tetramer formation affecting channel function

Kandel

Yamamoto

Midorikawa

et al. 2018

Journal of Neurochemistry

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The AMPA-type glutamate receptor (AMPA-R) plays a primary role in principal excitatory synaptic transmission and many neuronal functions including synaptic plasticity that underlie learning and memory. N-glycosylation is one of the major post-translational modifications of membrane proteins, but its specific roles in neurons remain largely unknown. AMPA-R subunits are N-glycosylated at their extracellular domains during their biosynthesis in the lumen of the endoplasmic reticulum and Golgi system. Six N-glycosylation sites are presumed to exist in the extracellular domain of GluA1, which is a member of the AMPA-R subunits. We observed that the intracellular trafficking and cell surface expression were strongly suppressed in the GluA1 mutants lacking N-glycans at N63/N363 in HEK293T cells. Multimer analysis using Blue Native-PAGE displayed the impaired tetramer formation in the glycosylation mutants (N63S and N363S), indicating that the mis-transport was caused by impaired tetramer formation. N63S and N363S mutants were primarily degraded via the lysosomal pathway. Flag-tagged N363S GluA1, but not N63S GluA1, expressed in primary cortical neuron cultures prepared from GluA1 knockout mice was observed to localize at the cell surface. Co-expression of GluA2 partially rescued tetramer formation and the cell surface expression of N363S GluA1 but not N63S GluA1, in HEK293T cells. Electrophysiological analysis also demonstrated functional heteromers of N363S GluA1 with GluA2. These data suggest that site-specific N-glycans on GluA1 subunit regulates tetramer formation, intracellular trafficking, and cell surface expression of AMPA-R. OPEN PRACTICES: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

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“…These changes are in stark contrast to the S2-M4 linkers in subunits B and D, which maintain their relative positioning. The unprecedented conformational changes in the subunits A/C S2-M4 linkers that occur during channel opening support the importance of the M4 segments for iGluR function 37–39 and suggest a possible contribution of these linkers to the open pore extracellular vestibule.…”

Section: Gating Mechanismmentioning

confidence: 81%

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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The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Cited by 24 publications

References 55 publications

The Structure of a High-Affinity Kainate Receptor: GluK4 Ligand-Binding Domain Crystallized with Kainate

The Structure of a High-Affinity Kainate Receptor: GluK4 Ligand-Binding Domain Crystallized with Kainate

N‐glycosylation of the AMPA‐type glutamate receptor regulates cell surface expression and tetramer formation affecting channel function

Channel opening and gating mechanism in AMPA-subtype glutamate receptors

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