Mechanisms underlying TARP modulation of the GluA1/2-y8 AMPA receptor

Herguedas, Beatriz (Universidad de Zaragoza) ; Kohegyi, Bianka K. ; Dohrke, Jan-Niklas ; Watson, Jake F. ; Zhang, Danyang ; Ho, Hinze ; Shaikh, Saher A. ; Lape, Remigijus ; Krieger, James M. ; Greger, Ingo H.

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/s41467-022-28404-7

Año: 2022

Publicado en: Nature communications 13, 734 (2022), 13
ISSN: 2041-1723

Factor impacto JCR: 16.6 (2022)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 6 / 73 = 0.082 (2022) - Q1 - T1

Factor impacto CITESCORE: 24.9 - Physics and Astronomy (Q1) - General (Q1) - Chemistry (Q1) - Biochemistry, Genetics and Molecular Biology (Q1)

Factor impacto SCIMAGO: 5.116 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1) - Physics and Astronomy (miscellaneous) (Q1) - Chemistry (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MCINN/AEI/RYC2018-025720-I
Financiación: info:eu-repo/grantAgreement/ES/MICINN-AEI/PID2019-106284GA-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)