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

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

作者地址："[Xie, Lingling; McDaniel, Miranda J.; Perszyk, Riley E.; Kim, Sukhan; Zhang, Jing; Nocilla, Kelsey A.; Sheikh, Rehan; Yuan, Hongjie; Myers, Scott J.; Traynelis, Stephen F.] Emory Univ, Dept Pharmacol & Chem Biol, Sch Med, 1510 Clifton Rd,NE, Atlanta, GA 30322 USA; [Kim, Sukhan; Yuan, Hongjie; Myers, Scott J.; Traynelis, Stephen F.] Emory Univ, Ctr Funct Evaluat Rare Variants CFERV, Sch Med, Atlanta, GA 30322 USA; [Cappuccio, Gerarda; Romano, Roberta] Univ Naples Federico II, Dept Translat Med, Sect Pediat, Via Pansini 5, I-80131 Naples, Italy; [Shapiro, Kevin A.] Univ Calif San Francisco, Memory & Aging Ctr, Sandler Neurosci Ctr, Dept Neurol,UCSF, San Francisco, CA USA; [Munoz-Cabello, Beatriz] Univ Hosp Virgen Del Rocio, Dept Pediat, Seville, Spain; [Sanchez-Lara, Pedro A.; Grand, Katheryn] Cedars Sinai Med Ctr, Dept Pediat, Div Med Genet, Los Angeles, CA USA; [Armengol, Lluis] Quantitat Genom Med Labs, SL qGenom, Barcelona, Spain; [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Dept Pediat, Div Pediat Neurol, Los Angeles, CA USA; [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA USA; [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Ctr Undiagnosed Patient, Los Angeles, CA USA; [Pierson, Tyler Mark] Cedars Sinai Med Ctr, Board Governors Regenerat Med Inst, Los Angeles, CA USA; [Traynelis, Stephen F.] Emory Neurodegenerat Dis Ctr, Atlanta, GA 30322 USA; [Xie, Lingling] Chongqing Med Univ, Dept Neurol, Childrens Hosp, Chongqing 400014, Peoples R China; [Cappuccio, Gerarda] Baylor Coll Med, Dept Pediat Neurol, Houston, TX USA; [Cappuccio, Gerarda] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX USA"

通信作者："Traynelis, SF (通讯作者)，Emory Univ, Dept Pharmacol & Chem Biol, Sch Med, 1510 Clifton Rd,NE, Atlanta, GA 30322 USA.; Traynelis, SF (通讯作者)，Emory Univ, Ctr Funct Evaluat Rare Variants CFERV, Sch Med, Atlanta, GA 30322 USA.; Traynelis, SF (通讯作者)，Emory Neurodegenerat Dis Ctr, Atlanta, GA 30322 USA."

来源：CELLULAR AND MOLECULAR LIFE SCIENCES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000960782900002

JCR分区：Q1

影响因子：6.2

年份：2023

卷号：80

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：Glutamate receptors; Channelopathy; GRIN; GluN; Pre-M1; Translational study

摘要："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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