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

George K E Umanah; Mehdi Ghasemi; Xiling Yin; Melissa Chang; Jin Wan Kim; Jianmin Zhang; Erica Ma; Leslie A Scarffe; Yun-Il Lee; Rong Chen; Kavya Tangella; Amy McNamara; Leire Abalde-Atristain; Mohamad A Dar; Samuel Bennett; Marisol Cortes; Shaida A Andrabi; Paschalis-Thomas Doulias; Harry Ischiropoulos; Ted M Dawson; Valina L Dawson

doi:10.1016/j.celrep.2020.108329

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.

Authors

George K E Umanah¹, Mehdi Ghasemi², Xiling Yin³, Melissa Chang⁴, Jin Wan Kim⁵, Jianmin Zhang⁶, Erica Ma⁷, Leslie A Scarffe⁸, Yun-Il Lee⁹, Rong Chen³, Kavya Tangella³, Amy McNamara³, Leire Abalde-Atristain¹⁰, Mohamad A Dar³, Samuel Bennett³, Marisol Cortes³, Shaida A Andrabi¹¹, Paschalis-Thomas Doulias¹², Harry Ischiropoulos¹³, Ted M Dawson¹⁴, Valina L Dawson¹⁵

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: gumanah1@jhmi.edu.
² Department of Neurology, University of Massachusetts School of Medicine, Worcester, MA 01655, USA.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ University of California, Irvine, School of Medicine, Irvine, CA 92697-3950, USA.
⁵ University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁶ Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Beijing 100005, China.
⁷ Johns Hopkins University Krieger School of Arts and Sciences, Baltimore, MD 21205, USA.
⁸ Division of Neurology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
⁹ Division of Biotechnology, Well Aging Research Center, DGIST, Daegu, Republic of Korea.
¹⁰ Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.
¹¹ Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¹² Department of Pediatrics, Children's Hospital of Philadelphia Research Institute, The University of Pennsylvania, Philadelphia, PA 19104, USA.
¹³ Department of Pediatrics, Children's Hospital of Philadelphia Research Institute, The University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pharmacology, The University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, University of Massachusetts School of Medicine, Worcester, MA 01655, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: tdawson@jhmi.edu.
¹⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, University of Massachusetts School of Medicine, Worcester, MA 01655, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: vdawson@jhmi.edu.

Abstract

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding