PMID- 37803141
OWN - NLM
STAT- MEDLINE
DCOM- 20240117
LR  - 20240410
IS  - 1745-7254 (Electronic)
IS  - 1671-4083 (Print)
IS  - 1671-4083 (Linking)
VI  - 45
IP  - 2
DP  - 2024 Feb
TI  - Adapting the endoplasmic reticulum proteostasis rescues epilepsy-associated NMDA 
      receptor variants.
PG  - 282-297
LID - 10.1038/s41401-023-01172-w [doi]
AB  - The GRIN genes encoding N-methyl-D-aspartate receptor (NMDAR) subunits are 
      remarkably intolerant to variation. Many pathogenic NMDAR variants result in 
      their protein misfolding, inefficient assembly, reduced surface expression, and 
      impaired function on neuronal membrane, causing neurological disorders including 
      epilepsy and intellectual disability. Here, we investigated the proteostasis 
      maintenance of NMDARs containing epilepsy-associated variations in the GluN2A 
      subunit, including M705V and A727T. In the transfected HEK293T cells, we showed 
      that the two variants were targeted to the proteasome for degradation and had 
      reduced functional surface expression. We demonstrated that the application of 
      BIX, a known small molecule activator of an HSP70 family chaperone BiP (binding 
      immunoglobulin protein) in the endoplasmic reticulum (ER), dose-dependently 
      enhanced the functional surface expression of the M705V and A727T variants in 
      HEK293T cells. Moreover, BIX (10 muM) increased the surface protein levels of the 
      M705V variant in human iPSC-derived neurons. We revealed that BIX promoted 
      folding, inhibited degradation, and enhanced anterograde trafficking of the M705V 
      variant by modest activation of the IRE1 pathway of the unfolded protein 
      response. Our results suggest that adapting the ER proteostasis network restores 
      the folding, trafficking, and function of pathogenic NMDAR variants, representing 
      a potential treatment for neurological disorders resulting from NMDAR 
      dysfunction.
CI  - (c) 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia 
      Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.
FAU - Zhang, Pei-Pei
AU  - Zhang PP
AD  - Department of Physiology and Biophysics, Case Western Reserve University School 
      of Medicine, Cleveland, OH, 44106, USA.
FAU - Benske, Taylor M
AU  - Benske TM
AD  - Department of Physiology and Biophysics, Case Western Reserve University School 
      of Medicine, Cleveland, OH, 44106, USA.
FAU - Ahn, Lucie Y
AU  - Ahn LY
AD  - Department of Genetics and Genome Sciences, Case Western Reserve University 
      School of Medicine, Cleveland, OH, 44106, USA.
FAU - Schaffer, Ashleigh E
AU  - Schaffer AE
AD  - Department of Genetics and Genome Sciences, Case Western Reserve University 
      School of Medicine, Cleveland, OH, 44106, USA.
FAU - Paton, James C
AU  - Paton JC
AD  - Research Centre for Infectious Diseases, Department of Molecular and Biomedical 
      Science, University of Adelaide, Adelaide, SA, 5005, Australia.
FAU - Paton, Adrienne W
AU  - Paton AW
AD  - Research Centre for Infectious Diseases, Department of Molecular and Biomedical 
      Science, University of Adelaide, Adelaide, SA, 5005, Australia.
FAU - Mu, Ting-Wei
AU  - Mu TW
AUID- ORCID: 0000-0002-6419-9296
AD  - Department of Physiology and Biophysics, Case Western Reserve University School 
      of Medicine, Cleveland, OH, 44106, USA. tingwei.mu@case.edu.
FAU - Wang, Ya-Juan
AU  - Wang YJ
AUID- ORCID: 0000-0002-3284-9012
AD  - Department of Physiology and Biophysics, Case Western Reserve University School 
      of Medicine, Cleveland, OH, 44106, USA. yajuan.wang@case.edu.
LA  - eng
GR  - F30 HD110088/HD/NICHD NIH HHS/United States
GR  - R01 NS117176/NS/NINDS NIH HHS/United States
GR  - R01 NS123524/NS/NINDS NIH HHS/United States
GR  - T32 GM007250/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20231006
PL  - United States
TA  - Acta Pharmacol Sin
JT  - Acta pharmacologica Sinica
JID - 100956087
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
SB  - IM
MH  - Humans
MH  - *Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Proteostasis
MH  - HEK293 Cells
MH  - *Epilepsy/genetics/metabolism
MH  - Endoplasmic Reticulum/metabolism
PMC - PMC10789767
OTO - NOTNLM
OT  - NMDA receptors
OT  - channelopathy
OT  - endoplasmic reticulum
OT  - epilepsy
OT  - proteostasis
OT  - unfolded protein response
COIS- The authors declare no competing interests.
EDAT- 2023/10/07 00:42
MHDA- 2024/01/17 06:42
PMCR- 2025/02/01
CRDT- 2023/10/06 23:28
PHST- 2023/04/03 00:00 [received]
PHST- 2023/09/17 00:00 [accepted]
PHST- 2025/02/01 00:00 [pmc-release]
PHST- 2024/01/17 06:42 [medline]
PHST- 2023/10/07 00:42 [pubmed]
PHST- 2023/10/06 23:28 [entrez]
AID - 10.1038/s41401-023-01172-w [pii]
AID - 1172 [pii]
AID - 10.1038/s41401-023-01172-w [doi]
PST - ppublish
SO  - Acta Pharmacol Sin. 2024 Feb;45(2):282-297. doi: 10.1038/s41401-023-01172-w. Epub 
      2023 Oct 6.