Allosteric competition and inhibition in AMPA receptors

W Dylan Hale; Alejandra Montaño Romero; Cuauhtemoc U Gonzalez; Vasanthi Jayaraman; Albert Y Lau; Richard L Huganir; Edward C Twomey

doi:10.1038/s41594-024-01328-0

Allosteric competition and inhibition in AMPA receptors

Nat Struct Mol Biol. 2024 Jun 4. doi: 10.1038/s41594-024-01328-0. Online ahead of print.

Authors

W Dylan Hale^{1

2}, Alejandra Montaño Romero^#^{1

2}, Cuauhtemoc U Gonzalez^#^{3

4}, Vasanthi Jayaraman³, Albert Y Lau⁵, Richard L Huganir^{6

7}, Edward C Twomey^{8

9

10

11}

Affiliations

¹ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Center for Membrane Biology, Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴ The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵ Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
⁶ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
⁷ Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
⁸ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
⁹ Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁰ The Beckman Center for Cryo-EM at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹¹ Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. [email protected].

^# Contributed equally.

PMID: 38834914
DOI: 10.1038/s41594-024-01328-0

Abstract

Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases.

Grants and funding

K99 MH132811/MH/NIMH NIH HHS/United States