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Instruments / Technical Area	Publication Details	Published
Krios IV-Titan Krios IV at Diamond	Architecture of the heteromeric GluA1/2 AMPA receptor in complex with the auxiliary subunit TARP γ8 Beatriz Herguedas , Jake F. Watson , Hinze Ho , Ondrej Cais , Javier Garcia-Nafria , Ingo H. Greger Science DOI: 10.1126/science.aav9011 Diamond Proposal Number(s): [17434] Show Abstract ▼ Abstract: AMPA-type glutamate receptors (AMPARs) mediate excitatory neurotransmission, and are central regulators of synaptic plasticity, a molecular mechanism underlying learning and memory. Although AMPARs act predominantly as heteromers, structural studies have focused on homomeric assemblies. Here we present a cryo-EM structure of the heteromeric GluA1/2 receptor associated with two TARP γ8 auxiliary subunits, the principle AMPAR complex at hippocampal synapses. Within the receptor, the core subunits arrange to give the GluA2 subunit dominant control of gating. This structure reveals the geometry of the Q/R-site controlling calcium flux, suggests association of TARP-stabilized lipids, and demonstrates that the extracellular loop of γ8 modulates gating by selectively interacting with the GluA2 ligand-binding domain. Collectively, this structure provides a blueprint for deciphering the signal transduction mechanisms of synaptic AMPARs.	Mar 2019
Krios I-Titan Krios I at Diamond	Gating and modulation of a hetero-octameric AMPA glutamate receptor Danyang Zhang , Jake F. Watson , Peter M. Matthews , Ondrej Cais , Ingo H. Greger Nature 62 DOI: 10.1038/s41586-021-03613-0 Diamond Proposal Number(s): [17434] Show Abstract ▼ Abstract: AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning. 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 strength. 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.	Jun 2021
Krios III-Titan Krios III at Diamond	Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor Beatriz Herguedas , Bianka K. Kohegyi , Jan-Niklas Dohrke , Jake F. Watson , Danyang Zhang , Hinze Ho , Saher A. Shaikh , Remigijus Lape , James M. Krieger , Ingo H. Greger Nature Communications 13 DOI: 10.1038/s41467-022-28404-7 Diamond Proposal Number(s): [23268] Open Access Show Abstract ▼ 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.	Feb 2022

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