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.
Highlights
AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain
The extracellular region (ECR) is comprised of the ligand-binding domain (LBD) and the N-terminal domain (NTD), both of which fold into bi-lobate ‘clamshell’ structures that are arranged as dimers of dimers[9,10]
Glutamate binding to the LBD triggers clamshell closure, which transmits to the transmembrane domain (TMD) to open the channel’s gate, or leads to desensitization through rupture of one or both LBD dimers[11]
Summary
AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the LBD triggers clamshell closure, which transmits to the transmembrane domain (TMD) to open the channel’s gate, or leads to desensitization through rupture of one or both LBD dimers[11] Both routes are believed to proceed in parallel from a short-lived, closed-clamshell transition state (Fig. 1a)[7], and are modulated by auxiliary subunits[5]. The smaller Type-1a TARPs (as well as cornichon subunits) can locate to both sites[14,17,23,24,25], while Type-1b TARPs (and GSG1l; germ-cell specific gene 1-like protein) preferentially associate with the spatially more accessible B′D′ sites (Fig. 1; right panels)[24,25] The rules underlying these distinct associations patterns are not resolved. These rules will determine the reach of the TARP loops for the LBDs, and centrally contribute to AMPAR modulation
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