ArticleThe Journal of pharmacology and experimental therapeutics2012
Compromising σ-1 receptors at the endoplasmic reticulum render cytotoxicity to physiologically relevant concentrations of dopamine in a nuclear factor-κB/Bcl-2-dependent mechanism: potential relevance to Parkinson's disease.
Article in The Journal of pharmacology and experimental therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 56 citations in OpenAlex.
- Memantine: updates from the past decade and implications for future novel therapeutic applications.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Targeting endoplasmic reticulum stress and protein misfolding in schizophrenia: the emerging promise of sigma-1 receptor agonists.Psychopharmacology · 2026Review
- Sigma-1 Receptor Ligands for CNS Cancer Treatment.CNS drugs · 2025Review
- Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders.ACS pharmacology & translational science · 2025Review
- Review
- Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders.CNS drugs · 2023Review
- Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection.International journal of molecular sciences · 2023Review
- Generation of Sigmar1 conditional knockout mouse using CRISPR-Cas9 gene targeting.Genesis (New York, N.Y. : 2000) · 2022Article
- Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish.International journal of molecular sciences · 2021Article
- Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy.Expert opinion on therapeutic targets · 2021Review
- The multi-functional RNA-binding protein G3BP1 and its potential implication in neurodegenerative disease.Journal of neurochemistry · 2021Review
- Review
- Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials.Journal of neural transmission (Vienna, Austria : 1996) · 2021Review
- Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes.Science (New York, N.Y.) · 2020Article
- Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration.Frontiers in neuroscience · 2020Review
- Effect ofEvidence-based complementary and alternative medicine : eCAM · 2020Article
- Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson's disease.Scientific reports · 2019Article
- The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer.Frontiers in neuroscience · 2019Review
- The Roles of Intracellular Chaperone Proteins, Sigma Receptors, in Parkinson's Disease (PD) and Major Depressive Disorder (MDD).Frontiers in pharmacology · 2019Review
- Unfolded Protein Response-Dependent Communication and Contact among Endoplasmic Reticulum, Mitochondria, and Plasma Membrane.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The endoplasmic reticulum (ER) chaperone σ-1 receptor (Sig-1R) is cytoprotective against ER stress-induced apoptosis. The level of Sig-1Rs in the brain was reported to be lower in early parkinsonian patients. Because dopamine (DA) toxicity is well known to be involved in the etiology of Parkinson's disease, we tested in this study whether a relationship might exist between Sig-1Rs and DA-induced cytotoxicity in a cellular model by using Chinese hamster ovary (CHO) cells. DA in physiological concentrations (e.g., lower than 10 μM) does not cause apoptosis. However, the same concentrations of DA cause apoptosis in Sig-1R knockdown CHO cells. In search of a mechanistic explanation, we found that unfolded protein response is not involved. Rather, the level of protective protein Bcl-2 is critically involved in this DA/Sig-1R knockdown-induced apoptosis. Specifically, the DA/Sig-1R knockdown causes a synergistic proteasomal conversion of nuclear factor κB (NF-κB) p105 to the active form of p50, which is known to down-regulate the transcription of Bcl-2. It is noteworthy that the DA/Sig-1R knockdown-induced apoptosis is blocked by the overexpression of Bcl-2. Our results therefore indicate that DA is involved in the activation of NF-κB and suggest that endogenous Sig-1Rs are tonically inhibiting the proteasomal conversion/activation of NF-κB caused by physiologically relevant concentrations of DA that would otherwise cause apoptosis. Thus, Sig-1Rs and associated ligands may represent new therapeutic targets for the treatment of parkinsonism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.