Details

Autor(en) / Beteiligte

• Twomey, Edward C.
• Yelshanskaya, Maria V.
• Grassucci, Robert A.
• Frank, Joachim
• Sobolevsky, Alexander I.

Titel

Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes

Ist Teil von

• Neuron (Cambridge, Mass.), 2017-05, Vol.94 (3), p.569-580.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Fast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits that modulate AMPAR assembly, trafficking, gating, and pharmacology. Aberrancies in AMPAR-mediated signaling are associated with numerous neurological disorders. Here, we report cryo-EM structures of an AMPAR in complex with the auxiliary subunit GSG1L in the closed and desensitized states. GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by profound structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local 2-fold rotational symmetry. Our structural and functional experiments suggest that AMPAR auxiliary subunits share a modular architecture and use a common transmembrane scaffold for distinct extracellular modules to differentially regulate AMPAR gating. By comparing the AMPAR-GSG1L complex structures, we map conformational changes accompanying AMPAR recovery from desensitization and reveal structural bases for regulation of synaptic transmission by auxiliary subunits. •Structures of AMPAR-auxiliary subunit complexes are solved in different gating states•Auxiliary subunits use common scaffolds and distinct modules to regulate AMPAR gating•Ligand binding domain layer changes symmetry and interfaces during desensitization•Amino terminal domain layer rotates and translates to accommodate these changes Auxiliary subunits tightly regulate AMPA receptor function in excitatory neurotransmission. Twomey et al. elucidate the structural bases for regulation of desensitization in AMPA receptor complexes, where profound changes in interfaces and symmetry of the synaptic receptor domains dictate gating kinetics.