Cytoprotective small molecule modulators of endoplasmic reticulum stress

Munshi, Soumyabrata; Dahl, Russell

doi:10.1016/j.bmc.2016.03.045

Cited by 4 publications

(1 citation statement)

References 39 publications

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“…The fact that several pathogenic mutations in the GluN subunits alter the surface delivery of NMDARs (Swanger et al, 2016;Addis et al, 2017;Chen et al, 2017;Liu et al, 2017;Ogden et al, 2017;Vyklicky et al, 2018;Skrenkova et al, 2020), further emphasizes the importance of understanding the molecular mechanisms regulating ER processing of NMDARs also under pathophysiological conditions. Given that a wide range of ER quality control (Munshi and Dahl, 2016;Zhou et al, 2018) and NMDAR (Traynelis et al, 2010;Strong et al, 2014) modulators are currently available, it is possible that one of the potential clinical treatments of patients with abnormal regulation of NMDARs could be pharmacologically induced alteration of the ER processing of the NMDARs.…”

Section: Discussionmentioning

confidence: 99%

The Extracellular Domains of GluN Subunits Play an Essential Role in Processing NMDA Receptors in the ER

et al. 2021

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N-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system (CNS). Functional NMDARs consist of heterotetramers comprised of GluN1, GluN2A-D, and/or GluN3A-B subunits, each of which contains four membrane domains (M1 through M4), an intracellular C-terminal domain, a large extracellular N-terminal domain composed of the amino-terminal domain and the S1 segment of the ligand-binding domain (LBD), and an extracellular loop between M3 and M4, which contains the S2 segment of the LBD. Both the number and type of NMDARs expressed at the cell surface are regulated at several levels, including their translation and posttranslational maturation in the endoplasmic reticulum (ER), intracellular trafficking via the Golgi apparatus, lateral diffusion in the plasma membrane, and internalization and degradation. This review focuses on the roles played by the extracellular regions of GluN subunits in ER processing. Specifically, we discuss the presence of ER retention signals, the integrity of the LBD, and critical N-glycosylated sites and disulfide bridges within the NMDAR subunits, each of these steps must pass quality control in the ER in order to ensure that only correctly assembled NMDARs are released from the ER for subsequent processing and trafficking to the surface. Finally, we discuss the effect of pathogenic missense mutations within the extracellular domains of GluN subunits with respect to ER processing of NMDARs.

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