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Functional effects of disease-associated variants reveal that the S1–M1 linker of the NMDA receptor critically controls channel opening

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Abstract

The short pre-M1 helix within the S1–M1 linker (also referred to as the pre-M1 linker) between the agonist-binding domain (ABD, S1) and the M1 transmembrane helix of the NMDA receptor (NMDAR) is devoid of missense variants within the healthy population but is a locus for de novo pathogenic variants associated with neurological disorders. Several de novo variants within this helix have been identified in patients presenting early in life with intellectual disability, developmental delay, and/or epilepsy. In this study, we evaluated functional properties for twenty variants within the pre-M1 linker in GRIN1, GRIN2A, and GRIN2B genes, including six novel missense variants. The effects of pre-M1 variants on agonist potency, sensitivity to endogenous allosteric modulators, response time course, channel open probability, and surface expression were assessed. Our data indicated that virtually all of the variants evaluated altered channel function, and multiple variants had profound functional consequences, which may contribute to the neurological conditions in the patients harboring the variants in this region. These data strongly suggest that the residues within the pre-M1 helix play a key role in channel gating and are highly intolerant to genetic variation.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

3DMTR:

Three-dimensional missense tolerance

7-CKA:

7-chlorokynurenic acid

ABD:

Agonist binding domain

AP-5:

d,l-2-amino-5-phosphonovalerate

ASD:

Autism spectrum disorder

ATD:

Amino-terminal domain

CTD:

Carboxyl-terminal domain

LBD:

Ligand binding domain

MTSEA:

2-aminoethyl methanethiosulfonate hydrobromide

NMDAR:

N-methyl-d-aspartate receptor

NTD:

N-terminal domain

TEVC:

Two-electrode voltage clamp

TMD:

Transmembrane domain (M1–4)

τW :

Weighted deactivation tau

WT:

Wildtype

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Acknowledgements

We thank Phoung Le for excellent technical assistance.

Funding

This work was supported by the CureGRIN Foundation (SFT), Simon’s Foundation (SFT), the NIH (NINDS NS111619 to SFT; NICHD HD082373 to HY, AG072142 to SJM), the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program (TMP), the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases (TMP), and the Cedars-Sinai institutional funding program (TMP).

Author information

Author notes

  1. Gerarda Cappuccio

    Present address: Section of Pediatrics, Department of Translational Medicine, Federico II University, Via Pansini 5, 80131, Naples, Italy

  2. Lingling Xie

    Present address: Department of Neurology, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, China

  3. Gerarda Cappuccio

    Present address: Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA

  4. Gerarda Cappuccio

    Present address: Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

Authors and Affiliations

  1. Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Road, NE, Atlanta, GA, 30322, USA

    Lingling Xie, Miranda J. McDaniel, Riley E. Perszyk, Sukhan Kim, Jing Zhang, Kelsey A. Nocilla, Rehan Sheikh, Hongjie Yuan, Scott J. Myers & Stephen F. Traynelis

  2. Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, 30322, USA

    Sukhan Kim, Hongjie Yuan, Scott J. Myers & Stephen F. Traynelis

  3. Section of Pediatrics, Department of Translational Medicine, Federico II University, Via Pansini 5, 80131, Naples, Italy

    Roberta Romano

  4. Department of Neurology, University of California, UCSF Memory and Aging Center, Sandler Neurosciences Center, San Francisco, CA, USA

    Kevin A. Shapiro

  5. Department of Pediatrics, University Hospital Virgen del Rocío, Seville, Spain

    Beatriz Muñoz-Cabello

  6. Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, USA

    Pedro A. Sanchez-Lara & Katheryn Grand

  7. Quantitative Genomic Medicine Laboratories, SL (qGenomics), Barcelona, Spain

    Lluis Armengol

  8. Division of Pediatric Neurology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, USA

    Tyler Mark Pierson

  9. Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, USA

    Tyler Mark Pierson

  10. Center for the Undiagnosed Patient, Cedars-Sinai Medical Center, Los Angeles, USA

    Tyler Mark Pierson

  11. Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA

    Tyler Mark Pierson

  12. Emory Neurodegenerative Disease Center, Atlanta, GA, 30322, USA

    Stephen F. Traynelis

Authors
  1. Lingling Xie
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  2. Miranda J. McDaniel
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  3. Riley E. Perszyk
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  4. Sukhan Kim
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  5. Gerarda Cappuccio
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  6. Kevin A. Shapiro
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  7. Beatriz Muñoz-Cabello
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  8. Pedro A. Sanchez-Lara
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  9. Katheryn Grand
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  10. Jing Zhang
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  11. Kelsey A. Nocilla
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  12. Rehan Sheikh
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  13. Lluis Armengol
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  14. Roberta Romano
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  15. Tyler Mark Pierson
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  16. Hongjie Yuan
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  17. Scott J. Myers
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  18. Stephen F. Traynelis
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Contributions

SFT, SJM, and HY designed the experiments and analyzed the data; GC, KAS, BMC, PAS, KG, LAD, RR and TMP contributed to phenotyping and collecting clinical information; LX, MJM, REP, SK, JZ, KN, RS, and SJM performed biological experiments. All authors discussed the results and implications. All authors wrote the manuscript and read and approved the final manuscript.

Corresponding author

Correspondence to Stephen F. Traynelis.

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Conflict of interest

SFT is a member of the SAB for Eumentis Therapeutics, Sage Therapeutics, and Combined Brain, is a member of the Medical Advisory Board for the GRIN2B Foundation and the CureGRIN Foundation, is an advisor to GRIN Therapeutics and Neurocrine, is co-founder of NeurOp Inc. and AgriThera Inc., and is a member of the Board of Directors of NeurOp Inc. HY is PI on a research grant from Sage Therapeutics to Emory University School of Medicine. SJM is PI on a research grant from GRIN Therapeutics to Emory University School of Medicine. SFT, SJM, and HY are co-inventors on Emory University-owned Intellectual Property that includes allosteric modulators of NMDA receptor function. TMP has no disclosures.

Ethics approval

This study was approved by the Medical Ethics Committee and the Institutional Review Boards of Federico II University (Italy), University of California, San Francisco (USA), University Hospital Virgen del Rocío (Spain), and Cedars-Sinai Medical Center (USA). All functional studies were performed according to the guidelines of Emory University.

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Xie, L., McDaniel, M.J., Perszyk, R.E. et al. Functional effects of disease-associated variants reveal that the S1–M1 linker of the NMDA receptor critically controls channel opening. Cell. Mol. Life Sci. 80, 110 (2023). https://doi.org/10.1007/s00018-023-04705-y

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  • DOI: https://doi.org/10.1007/s00018-023-04705-y

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