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

Lingling Xie; Miranda J McDaniel; Riley E Perszyk; Sukhan Kim; Gerarda Cappuccio; Kevin A Shapiro; Beatriz Muñoz-Cabello; Pedro A Sanchez-Lara; Katheryn Grand; Jing Zhang; Kelsey A Nocilla; Rehan Sheikh; Lluis Armengol; Roberta Romano; Tyler Mark Pierson; Hongjie Yuan; Scott J Myers; Stephen F Traynelis

doi:10.1007/s00018-023-04705-y

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

Cell Mol Life Sci. 2023 Mar 31;80(4):110. doi: 10.1007/s00018-023-04705-y.

Authors

Lingling Xie^{1

2}, Miranda J McDaniel¹, Riley E Perszyk¹, Sukhan Kim^{1

3}, Gerarda Cappuccio^{4

5

6}, Kevin A Shapiro⁷, Beatriz Muñoz-Cabello⁸, Pedro A Sanchez-Lara⁹, Katheryn Grand⁹, Jing Zhang¹, Kelsey A Nocilla¹, Rehan Sheikh¹, Lluis Armengol¹⁰, Roberta Romano⁴, Tyler Mark Pierson^{11

12

13

14}, Hongjie Yuan^{1

3}, Scott J Myers^{1

3}, Stephen F Traynelis^{15

16

17}

Affiliations

¹ Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Road, NE, Atlanta, GA, 30322, USA.
² Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
³ Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, 30322, USA.
⁴ Section of Pediatrics, Department of Translational Medicine, Federico II University, Via Pansini 5, 80131, Naples, Italy.
⁵ Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA.
⁶ Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
⁷ Department of Neurology, University of California, UCSF Memory and Aging Center, Sandler Neurosciences Center, San Francisco, CA, USA.
⁸ Department of Pediatrics, University Hospital Virgen del Rocío, Seville, Spain.
⁹ Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, USA.
¹⁰ Quantitative Genomic Medicine Laboratories, SL (qGenomics), Barcelona, Spain.
¹¹ Division of Pediatric Neurology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, USA.
¹² Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, USA.
¹³ Center for the Undiagnosed Patient, Cedars-Sinai Medical Center, Los Angeles, USA.
¹⁴ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
¹⁵ Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Road, NE, Atlanta, GA, 30322, USA. strayne@emory.edu.
¹⁶ Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, 30322, USA. strayne@emory.edu.
¹⁷ Emory Neurodegenerative Disease Center, Atlanta, GA, 30322, USA. strayne@emory.edu.

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.

Keywords: Channelopathy; GRIN; GluN; Glutamate receptors; Pre-M1; Translational study.

MeSH terms

Epilepsy* / genetics
Humans
Intellectual Disability*
Mutation, Missense / genetics
Receptors, N-Methyl-D-Aspartate* / metabolism

Substances

Receptors, N-Methyl-D-Aspartate
GRIN1 protein, human
N-methyl D-aspartate receptor subtype 2A
NR2B NMDA receptor

Abstract

MeSH terms

Substances

Grants and funding