--- res: bibo_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. @eng bibo_authorlist: - foaf_Person: foaf_givenName: Danyang foaf_name: Zhang, Danyang foaf_surname: Zhang - foaf_Person: foaf_givenName: Jake foaf_name: Watson, Jake foaf_surname: Watson foaf_workInfoHomepage: http://www.librecat.org/personId=63836096-4690-11EA-BD4E-32803DDC885E orcid: 0000-0002-8698-3823 - foaf_Person: foaf_givenName: Peter M. foaf_name: Matthews, Peter M. foaf_surname: Matthews - foaf_Person: foaf_givenName: Ondrej foaf_name: Cais, Ondrej foaf_surname: Cais - foaf_Person: foaf_givenName: Ingo H. foaf_name: Greger, Ingo H. foaf_surname: Greger bibo_doi: 10.1038/s41586-021-03613-0 bibo_volume: 594 dct_date: 2021^xs_gYear dct_identifier: - UT:000657238100003 dct_isPartOf: - http://id.crossref.org/issn/0028-0836 - http://id.crossref.org/issn/1476-4687 dct_language: eng dct_publisher: Springer Nature@ dct_title: Gating and modulation of a hetero-octameric AMPA glutamate receptor@ fabio_hasPubmedId: '34079129' ...