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

• Type of Material: Article
• Authors: Lingling Xie, Emory University; Miranda J. McDaniel, Emory University; Riley E. Perszyk, Emory University; Sukhan Kim, Emory University; Gerarda Cappuccio, Federico II University; Kevin A. Shapiro, University of California, San Francisco; Beatriz Muñoz-Cabello, University Hospital Virgen del Rocio; Pedro a. Sanchez-Lara, Cedars-Sinai Medical Center; Katheryn Grand, Cedars-Sinai Medical Center; Jing Zhang, Emory University; Kelsey A. Nocilla, Emory University; Rehan Sheikh, Emory University; Lluis Armengol, Quantitative Genomic Medicine Laboratories; Roberta Romano, Federico II University; Tyler Mark Pierson, Cedars-Sinai Medical Center; Hongjie Yuan, Emory University; Scott J Myers, Emory University; Stephen Traynelis, Emory University
• Language: English
• Date: 2023-03-31
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG
• Final Published Version (URL): https://doi.org/10.1007/s00018-023-04705-y
• Title of Journal or Parent Work: Cellular and Molecular Life Sciences
• Volume: 80
• Issue: 4
• Start Page: 110
• Grant/Funding Information: 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).
• Keywords: Channelopathy; Glutamate receptors; GluN; GRIN; Pre-M1; Translational study
• Research Categories: Biology, Genetics; Biology, Neuroscience

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.