AMPA Receptor Surface Expression Is Regulated by S-Nitrosylation of Thorase and Transnitrosylation of NSF

Cell Rep. 2020 Nov 3;33(5):108329. doi: 10.1016/j.celrep.2020.108329.


The regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking affects multiple brain functions, such as learning and memory. We have previously shown that Thorase plays an important role in the internalization of AMPARs from the synaptic membrane. Here, we show that N-methyl-d-aspartate receptor (NMDAR) activation leads to increased S-nitrosylation of Thorase and N-ethylmaleimide-sensitive factor (NSF). S-nitrosylation of Thorase stabilizes Thorase-AMPAR complexes and enhances the internalization of AMPAR and interaction with protein-interacting C kinase 1 (PICK1). S-nitrosylated NSF is dependent on the S-nitrosylation of Thorase via trans-nitrosylation, which modulates the surface insertion of AMPARs. In the presence of the S-nitrosylation-deficient C137L Thorase mutant, AMPAR trafficking, long-term potentiation, and long-term depression are impaired. Overall, our data suggest that both S-nitrosylation and interactions of Thorase and NSF/PICK1 are required to modulate AMPAR-mediated synaptic plasticity. This study provides critical information that elucidates the mechanism underlying Thorase and NSF-mediated trafficking of AMPAR complexes.

Keywords: AMPAR; ATAD1; GluA2; N-ethylmaleimide-sensitive factor; N-methyl-d-aspartate receptor; NMDAR; NSF; PICK1; S-nitrosylation; endocytosis; exocytosis; protein-interacting C kinase 1; thorase; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / metabolism*
  • Adenosine Triphosphatases / metabolism
  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Membrane / metabolism*
  • Cysteine / metabolism
  • Endocytosis / drug effects
  • Glutathione / metabolism
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Mice, Knockout
  • N-Ethylmaleimide-Sensitive Proteins / metabolism*
  • N-Methylaspartate / pharmacology
  • Neuronal Plasticity
  • Nitric Oxide / metabolism
  • Nitrosation
  • Protein Binding
  • Protein Multimerization
  • Protein Transport
  • Receptors, AMPA / metabolism*
  • S-Nitrosoglutathione / metabolism


  • Cell Cycle Proteins
  • Prkcabp protein, mouse
  • Receptors, AMPA
  • Nitric Oxide
  • S-Nitrosoglutathione
  • N-Methylaspartate
  • Adenosine Triphosphatases
  • ATAD1 protein, mouse
  • ATPases Associated with Diverse Cellular Activities
  • N-Ethylmaleimide-Sensitive Proteins
  • Glutathione
  • Cysteine