1. Mechanisms underlying TARP modulation of the GluA1/2-y8 AMPA receptor
- Author
-
Herguedas, Beatriz, Kohegyi, Bianka K, Dohrke, Jan-Niklas, Watson, Jake F, Zhang, Danyang, Ho, Hinze, Shaikh, Saher A, Lape, Remigijus, Krieger, James M, Greger, Ingo H, Herguedas, Beatriz [0000-0003-2044-4795], Watson, Jake F [0000-0002-8698-3823], Ho, Hinze [0000-0003-1082-9851], Shaikh, Saher A [0000-0002-6162-5472], Krieger, James M [0000-0001-6194-6244], Greger, Ingo H [0000-0002-7291-2581], and Apollo - University of Cambridge Repository
- Subjects
Patch-Clamp Techniques ,101 ,631/535/1258/1259 ,Science ,Glutamic Acid ,General Physics and Astronomy ,Transfection ,13 ,Synaptic Transmission ,General Biochemistry, Genetics and Molecular Biology ,Protein Domains ,Animals ,Humans ,Receptors, AMPA ,Multidisciplinary ,musculoskeletal, neural, and ocular physiology ,Cryoelectron Microscopy ,9/74 ,101/28 ,article ,General Chemistry ,Recombinant Proteins ,Rats ,631/45/269/1149 ,HEK293 Cells ,nervous system ,631/57/2283 ,Mutation ,9 ,631/378/2586 ,Calcium Channels - Abstract
AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the receptor’s ligand-binding domains (LBDs) leads to ion channel activation and desensitization. Gating kinetics shape synaptic transmission and are strongly modulated by transmembrane AMPAR regulatory proteins (TARPs) through currently incompletely resolved mechanisms. Here, electron cryo-microscopy structures of the GluA1/2 TARP-γ8 complex, in both open and desensitized states (at 3.5 Å), reveal state-selective engagement of the LBDs by the large TARP-γ8 loop (‘β1’), elucidating how this TARP stabilizes specific gating states. We further show how TARPs alter channel rectification, by interacting with the pore helix of the selectivity filter. Lastly, we reveal that the Q/R-editing site couples the channel constriction at the filter entrance to the gate, and forms the major cation binding site in the conduction path. Our results provide a mechanistic framework of how TARPs modulate AMPAR gating and conductance.
- Published
- 2022