The regulatory role of endoplasmic reticulum chaperone proteins in neurodevelopment

Sun, Honghao; Wu, Minxian; Wang, Minxin; Zhang, Xiaomin; Zhu, Jia

doi:10.3389/fnins.2022.1032607

Cited by 3 publications

(1 citation statement)

References 281 publications

(407 reference statements)

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“…Ligands that bind to the S1R regulate conversion of oligomeric (antagonist) to protomeric (agonist) forms [ 3 , 4 ]. This biochemical mechanism is similar to soluble small heat shock protein (sHSP) chaperones in which large oligomer-to-dimer conversions are activated by cellular stress (heat shock) instead of ligands [ 5 , 6 , 7 , 8 ]. The S1R is located mainly in specialized intracellular endoplasmic reticulum (ER) membranes (mitochondrial-associated membranes (MAM)) [ 1 ], but also in the ER, lysosomal, golgi, nucleoplasmic reticulum [ 9 ], and plasma membranes [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Sphingoid Bases Regulate the Sigma-1 Receptor—Sphingosine and N,N’-Dimethylsphingosine Are Endogenous Agonists

Satyshur

Ruoho

2023

IJMS

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Both bioactive sphingolipids and Sigma-1 receptor (S1R) chaperones occur ubiquitously in mammalian cell membranes. Endogenous compounds that regulate the S1R are important for controlling S1R responses to cellular stress. Herein, we interrogated the S1R in intact Retinal Pigment Epithelial cells (ARPE-19) with the bioactive sphingoid base, sphingosine (SPH), or the pain-provoking dimethylated SPH derivative, N,N-dimethylsphingosine (DMS). As informed by a modified native gel approach, the basal and antagonist (BD-1047)-stabilized S1R oligomers dissociated to protomeric forms in the presence of SPH or DMS (PRE-084 as control). We, thus, posited that SPH and DMS are endogenous S1R agonists. Consistently, in silico docking of SPH and DMS to the S1R protomer showed strong associations with Asp126 and Glu172 in the cupin beta barrel and extensive van der Waals interactions of the C18 alkyl chains with the binding site including residues in helices 4 and 5. Mean docking free energies were 8.73–8.93 kcal/mol for SPH and 8.56–8.15 kcal/mol for DMS, and calculated binding constants were ~40 nM for SPH and ~120 nM for DMS. We hypothesize that SPH, DMS, and similar sphingoid bases access the S1R beta barrel via a membrane bilayer pathway. We further propose that the enzymatic control of ceramide concentrations in intracellular membranes as the primary sources of SPH dictates availability of endogenous SPH and DMS to the S1R and the subsequent control of S1R activity within the same cell and/or in cellular environments.

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Section: Introductionmentioning

confidence: 99%

Sphingoid Bases Regulate the Sigma-1 Receptor—Sphingosine and N,N’-Dimethylsphingosine Are Endogenous Agonists

Satyshur

Ruoho

2023

IJMS

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Spatiotemporally Controllable Covalent Bonding of RNA for Multi‐Protein Interference

Fang,

Wang,

Dai

et al. 2024

Adv Healthcare Materials

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Many diseases are associated with genetic mutation and expression of mutated proteins, such as cancers. Therapeutic approaches that selectively target the synthesis process of multiple proteins show greater potential compared to single‐protein approaches in oncological diseases. However, conventional agents to regulate the synthesis of multiple protein still suffer from poor spatiotemporal selectivity and stability. Here, a new method using a dye‐peptide conjugate, PRFK, for multi‐protein interference with spatiotemporal selectivity and reliable stability, is reported. By using the peptide sequence that targets tumor cells, PRFK can be efficiently taken up, followed by specific binding to the KDELR (KDEL receptor) protein located in the endoplasmic reticulum (ER). The dye generates 1O2 under light irradiation, enabling photodynamic therapy. This process converts the furan group into a cytidine‐reactive intermediate, which covalently binds to mRNA, thereby blocking protein synthesis. Upon treating 4T1 cells, the proteomics data show alterations in apoptosis, ferroptosis, proliferation, migration, invasion, and immune infiltration, suggesting that multi‐protein interference leads to the disruption of cellular physiological activities, ultimately achieving tumor treatment. This study presents a multi‐protein interference probe with the potential for protein interference within various subcellular organelles in the future.

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Effects of Antipsychotics on the Hypothalamus–Pituitary–Adrenal Axis in a Phencyclidine Animal Model of Schizophrenia

Nikolić,

Bogosavljević,

Stojković

et al. 2024

Cells

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Schizophrenia (SCH) is a mental disorder that requires long-term antipsychotic treatment. SCH patients are thought to have an increased sensitivity to stress. The dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, observed in SCH, could include altered levels of glucocorticoids, glucocorticoid receptors (GRs), and associated proteins. The perinatal administration of phencyclidine (PCP) to rodents represents an animal model of SCH. This study investigated the effects of perinatal PCP exposure and subsequent haloperidol/clozapine treatment on corticosterone levels measured by ELISA and the expression of GR-related proteins (GR, pGR, HSP70, HSP90, FKBP51, and 11β-Hydroxysteroid dehydrogenase-11β-HSD) determined by Western blot, in different brain regions of adult rats. Six groups of male rats were treated on the 2nd, 6th, 9th, and 12th postnatal days (PN), with either PCP or saline. Subsequently, one saline and one PCP group received haloperidol/clozapine from PN day 35 to PN day 100. The results showed altered GR sensitivity in the rat brain after PCP exposure, which decreased after haloperidol/clozapine treatment. These findings highlight disturbances in the HPA axis in a PCP-induced model of SCH and the potential protective effects of antipsychotics. To the best of our knowledge, this is the first study to investigate the effects of antipsychotic drugs on the HPA axis in a PCP animal model of SCH.

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The regulatory role of endoplasmic reticulum chaperone proteins in neurodevelopment

Cited by 3 publications

References 281 publications

Sphingoid Bases Regulate the Sigma-1 Receptor—Sphingosine and N,N’-Dimethylsphingosine Are Endogenous Agonists

Sphingoid Bases Regulate the Sigma-1 Receptor—Sphingosine and N,N’-Dimethylsphingosine Are Endogenous Agonists

Spatiotemporally Controllable Covalent Bonding of RNA for Multi‐Protein Interference

Effects of Antipsychotics on the Hypothalamus–Pituitary–Adrenal Axis in a Phencyclidine Animal Model of Schizophrenia

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