TY - JOUR
T1 - Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes
AU - Twomey, Edward C.
AU - Yelshanskaya, Maria V.
AU - Grassucci, Robert A.
AU - Frank, Joachim
AU - Sobolevsky, Alexander I.
N1 - Funding Information:
We thank Bernd Fakler (University of Freiburg) for providing the GSG1L cDNA, and Z.H. Yu, C. Hong, and R. Huang for assistance with data collection at the HHMI Janelia Research Campus, H. Kao (J.F. Lab) for computational support, Israel S. Fernandez (Columbia University) for lending computational resources and processing advice, M. Fislage (J.F. lab) and F. Acosta-Reyes (J.F. Lab) for processing advice. We are grateful for manuscript edits and comments provided by A.K. Singh (A.I.S. lab) and A.G. Malyutin (J.F. lab). E.C.T. is currently supported by NIH (F31 NS093838) and was supported by NIH training grants (T32 GM008224 and GM008281) for part of this work. A.I.S. is supported by NIH (R01 NS083660, R01 CA206573), the Pew Scholar Award in Biomedical Sciences, and the Irma T. Hirschl Career Scientist Award. J.F. is supported by the Howard Hughes Medical Institute and NIH (R01 GM029169).
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/5/3
Y1 - 2017/5/3
N2 - 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.
AB - 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.
KW - AMPA receptor
KW - Excitatory neurotransmission
KW - auxiliary subunit
KW - cryo-electron microscopy
KW - desensitization
KW - gating
KW - glutamate receptor
KW - glutamatergic signaling
KW - neurodegenerative disease
KW - synaptic complex
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U2 - 10.1016/j.neuron.2017.04.025
DO - 10.1016/j.neuron.2017.04.025
M3 - Article
C2 - 28472657
AN - SCOPUS:85018783749
SN - 0896-6273
VL - 94
SP - 569-580.e5
JO - Neuron
JF - Neuron
IS - 3
ER -