Synaptic Dysfunction by Mutations in GRIN2B: Influence of Triheteromeric NMDA Receptors on Gain-of-Function and Loss-of-Function Mutant Classification

被引:10
|
作者
Elmasri, Marwa [1 ]
Lotti, James S. [2 ]
Aziz, Wajeeha [1 ]
Steele, Oliver G. [1 ]
Karachaliou, Eirini [1 ]
Sakimura, Kenji [3 ]
Hansen, Kasper B. [2 ]
Penn, Andrew C. [1 ]
机构
[1] Univ Sussex, Sussex Neurosci, Sch Life Sci, Brighton BN1 9QG, E Sussex, England
[2] Univ Montana, Ctr Struct & Funct Neurosci, Ctr Biomol Struct & Dynam, Div Biol Sci, Missoula, MT 59812 USA
[3] Niigata Univ, Dept Cellular Neurobiol, Brain Res Inst, Niigata 9518585, Japan
基金
英国医学研究理事会; 美国国家卫生研究院;
关键词
ionotropic glutamate receptors; de novo mutations; central nervous system; synaptic transmission; electrophysiology; D-ASPARTATE RECEPTORS; GLUTAMATE BINDING; LIGAND-BINDING; PATTERN-FORMATION; POINT MUTATIONS; QUALITY-CONTROL; RARE VARIANTS; HIPPOCAMPAL; SUBUNIT; GLUN2B;
D O I
10.3390/brainsci12060789
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
GRIN2B mutations are rare but often associated with patients having severe neurodevelopmental disorders with varying range of symptoms such as intellectual disability, developmental delay and epilepsy. Patient symptoms likely arise from mutations disturbing the role that the encoded NMDA receptor subunit, GluN2B, plays at neuronal connections in the developing nervous system. In this study, we investigated the cell-autonomous effects of putative gain- (GoF) and loss-of-function (LoF) missense GRIN2B mutations on excitatory synapses onto CA1 pyramidal neurons in organotypic hippocampal slices. In the absence of both native GluN2A and GluN2B subunits, functional incorporation into synaptic NMDA receptors was attenuated for GoF mutants, or almost eliminated for LoF GluN2B mutants. NMDA-receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) from synaptic GoF GluN1/2B receptors had prolonged decays consistent with their functional classification. Nonetheless, in the presence of native GluN2A, molecular replacement of native GluN2B with GoF and LoF GluN2B mutants all led to similar functional incorporation into synaptic receptors, more rapidly decaying NMDA-EPSCs and greater inhibition by TCN-201, a selective antagonist for GluN2A-containing NMDA receptors. Mechanistic insight was gained from experiments in HEK293T cells, which revealed that GluN2B GoF mutants slowed deactivation in diheteromeric GluN1/2B, but not triheteromeric GluN1/2A/2B receptors. We also show that a disease-associated missense mutation, which severely affects surface expression, causes opposing effects on NMDA-EPSC decay and charge transfer when introduced into GluN2A or GluN2B. Finally, we show that having a single null Grin2b allele has only a modest effect on NMDA-EPSC decay kinetics. Our results demonstrate that functional incorporation of GoF and LoF GluN2B mutants into synaptic receptors and the effects on EPSC decay times are highly dependent on the presence of triheteromeric GluN1/2A/2B NMDA receptors, thereby influencing the functional classification of NMDA receptor variants as GoF or LoF mutations. These findings highlight the complexity of interpreting effects of disease-causing NMDA receptor missense mutations in the context of neuronal function.
引用
收藏
页数:24
相关论文
共 50 条
  • [1] Opportunities for Precision Treatment of GRIN2A and GRIN2B Gain-of-Function Variants in Triheteromeric N-Methyl-D-Aspartate Receptors
    Han, Wei
    Yuan, Hongjie
    Allen, James P.
    Kim, Sukhan
    Shaulsky, Gil H.
    Perszyk, Riley E.
    Traynelis, Stephen F.
    Myers, Scott J.
    [J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2022, 381 (01): : 54 - 66
  • [2] Effects of GluN2A and GluN2B gain-of-function epilepsy mutations on synaptic currents mediated by diheteromeric and triheteromeric NMDA receptors
    Chen, Xiumin
    Keramidas, Angelo
    Harvey, Robert J.
    Lynch, Joseph W.
    [J]. NEUROBIOLOGY OF DISEASE, 2020, 140
  • [3] GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors
    Mullier, Brice
    Wolff, Christian
    Sands, Zara Amanda
    Ghisdal, Philippe
    Muglia, Pierandrea
    Kaminski, Rafal Marian
    Andre, Veronique Marie
    [J]. NEUROPHARMACOLOGY, 2017, 123 : 322 - 331
  • [4] NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations
    Bend, Eric G.
    Si, Yue
    Stevenson, David A.
    Bayrak-Toydemir, Pinar
    Newcomb, Tara M.
    Jorgensen, Erik M.
    Swoboda, Kathryn J.
    [J]. NEUROLOGY, 2016, 87 (11) : 1131 - 1139
  • [5] Loss-of-Function and Gain-of-Function Consequences of GATA2 Disease Mutations
    Katsumura, Koichi Ricardo
    Liu, Peng
    Mehta, Charu
    Hewitt, Kyle J.
    Soukup, Alexandra
    de Andrade, Isabela J. Fraga
    Ranheim, Erik A.
    Johnson, Kirby D.
    Bresnick, Emery H.
    [J]. BLOOD, 2019, 134
  • [6] Rescuing tri-heteromeric NMDA receptor function: the potential of pregnenolone-sulfate in loss-of-function GRIN2B variants
    Kellner, Shai
    Berlin, Shai
    [J]. CELLULAR AND MOLECULAR LIFE SCIENCES, 2024, 81 (01)
  • [7] Analysis of sperm galactosyltransferase through gain-of-function and loss-of-function mutations
    Shur, B
    Lu, QX
    Shi, XD
    Paruchuru, K
    Miller, D
    [J]. MOLECULAR BIOLOGY OF THE CELL, 1998, 9 : 7A - 7A
  • [8] Using SIFT and PolyPhen to Predict Loss-of-Function and Gain-of-Function Mutations
    Flanagan, Sarah E.
    Patch, Ann-Marie
    Ellard, Sian
    [J]. GENETIC TESTING AND MOLECULAR BIOMARKERS, 2010, 14 (04) : 533 - 537
  • [9] Prediction of gain-of-function and loss-of-function mutations using In Silico Bioinformatics Tools
    Ghosh, A.
    Navarini, A.
    [J]. EXPERIMENTAL DERMATOLOGY, 2018, 27 (03) : E41 - E41
  • [10] JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences
    Nils Ott
    Laura Faletti
    Maximilian Heeg
    Virginia Andreani
    Bodo Grimbacher
    [J]. Journal of Clinical Immunology, 2023, 43 : 1326 - 1359