Structural mobility tunes signalling of the GluA1 AMPA glutamate receptor

Abstract

Acknowledgements: We thank G. Murshudov for suggestions for model building and S. Scheres for comments on EM processing. We also thank B. Singh and J. Watson for comments on the manuscript. We acknowledge S. Nayak for help with Fig. 4e design and L. Catapano for help with Coot images in Extended Data Figs. 4 and 6. We are grateful to LMB Scientific Computing and the EM Facility for support. This work was supported by grants from the Medical Research Council (grant no. MC_U105174197) and the Wellcome Trust (grant no. 223194/Z/21/Z) to I.H.G., and H2020 Marie Skłodowska-Curie Actions (grant no. 101024130) to J.M.K.AMPA glutamate receptors (AMPARs), the primary mediators of excitatory neurotransmission in the brain, are either GluA2 subunit-containing and thus Ca2+-impermeable, or GluA2-lacking and Ca2+-permeable1. Despite their prominent expression throughout interneurons and glia, their role in long-term potentiation and their involvement in a range of neuropathologies2, structural information for GluA2-lacking receptors is currently absent. Here we determine and characterize cryo-electron microscopy structures of the GluA1 homotetramer, fully occupied with TARPγ3 auxiliary subunits (GluA1/γ3). The gating core of both resting and open-state GluA1/γ3 closely resembles GluA2-containing receptors. However, the sequence-diverse N-terminal domains (NTDs) give rise to a highly mobile assembly, enabling domain swapping and subunit re-alignments in the ligand-binding domain tier that are pronounced in desensitized states. These transitions underlie the unique kinetic properties of GluA1. A GluA2 mutant (F231A) increasing NTD dynamics phenocopies this behaviour, and exhibits reduced synaptic responses, reflecting the anchoring function of the AMPAR NTD at the synapse. Together, this work underscores how the subunit-diverse NTDs determine subunit arrangement, gating properties and ultimately synaptic signalling efficiency among AMPAR subtypes

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