Gating and modulation of a hetero-octameric AMPA glutamate receptor

Zhang D, Watson J, Matthews PM, Cais O, Greger IH. 2021. Gating and modulation of a hetero-octameric AMPA glutamate receptor. Nature.

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Journal Article | Epub ahead of print | English

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Author
Zhang, Danyang; Watson, JakeIST Austria; Matthews, Peter M.; Cais, Ondrej; Greger, Ingo H.
Department
Abstract
AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning1. A diverse array of AMPAR signalling complexes are established by receptor auxiliary subunits, which associate with the AMPAR in various combinations to modulate trafficking, gating and synaptic strength2. However, their mechanisms of action are poorly understood. Here we determine cryo-electron microscopy structures of the heteromeric GluA1–GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR complex in the forebrain, in both resting and active states. Two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of the receptor, with site-specific lipids shaping each interaction and affecting the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry between GluA1 and GluA2 along the ion conduction path and an outward expansion of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards the pore exit upon activation, extending their reach for cytoplasmic receptor elements. CNIH2 achieves this through its uniquely extended M2 helix, which has transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator that is capable of providing hippocampal pyramidal neurons with their integrative synaptic properties.
Publishing Year
Date Published
2021-06-02
Journal Title
Nature
Acknowledgement
We thank members of the Greger laboratory, B. Herguedas, J. Krieger and J.-N. Dohrke for comments on the manuscript; J. Krieger and J.-N. Dohrke for discussion, J. Krieger for help with the normal mode analysis, B. Köhegyi for help with cryo-EM imaging, V. Chang and K. Suzuki for helping to generate the CNIH2-1D4-HA stable cell line, M. Carvalho for assistance at early stages of this project, the LMB scientific computing and the cryo-EM facility for support, P. Emsley for help with model building, T. Nakane for helpful comments with RELION 3.1 and R. Warshamanage for helping with EMDA cryo-EM-map processing. We acknowledge the Diamond Light Source for access and support of the Cryo-EM facilities at the UK national electron bio10 imaging centre (eBIC), proposal EM17434, funded by the Wellcome Trust, MRC and BBSRC. This work was supported by grants from the Medical Research Council, as part of United Kingdom Research and Innovation (also known as UK Research and Innovation) (MC_U105174197) and BBSRC (BB/N002113/1) to I.H.G.
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Zhang D, Watson J, Matthews PM, Cais O, Greger IH. Gating and modulation of a hetero-octameric AMPA glutamate receptor. Nature. 2021. doi:10.1038/s41586-021-03613-0
Zhang, D., Watson, J., Matthews, P. M., Cais, O., & Greger, I. H. (2021). Gating and modulation of a hetero-octameric AMPA glutamate receptor. Nature. Springer Nature. https://doi.org/10.1038/s41586-021-03613-0
Zhang, Danyang, Jake Watson, Peter M. Matthews, Ondrej Cais, and Ingo H. Greger. “Gating and Modulation of a Hetero-Octameric AMPA Glutamate Receptor.” Nature. Springer Nature, 2021. https://doi.org/10.1038/s41586-021-03613-0.
D. Zhang, J. Watson, P. M. Matthews, O. Cais, and I. H. Greger, “Gating and modulation of a hetero-octameric AMPA glutamate receptor,” Nature. Springer Nature, 2021.
Zhang D, Watson J, Matthews PM, Cais O, Greger IH. 2021. Gating and modulation of a hetero-octameric AMPA glutamate receptor. Nature.
Zhang, Danyang, et al. “Gating and Modulation of a Hetero-Octameric AMPA Glutamate Receptor.” Nature, Springer Nature, 2021, doi:10.1038/s41586-021-03613-0.

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