Ischemia induces regulator of G protein signaling 2 (RGS2) protein upregulation and enhances apoptosis in astrocytes
Abstract
Regulator of G protein signaling (RGS) family members, such as RGS2, interact with Gα subunits of heterotrimeric G proteins, accelerating the rate of GTP hydrolysis and attenuating the intracellular signaling triggered by the G protein-coupled receptor-ligand interaction. They are also reported to regulate G protein-effector interactions and form multiprotein signaling complexes. Ischemic stress-induced changes in RGS2 expression have been described in astrocytes, and these changes are associated with intracellular signaling cascades, suggesting that RGS2 upregulation may be an important mechanism by which astrocytes may regulate RGS2 function in response to physiological stress. However, information on the functional roles of stress-induced modulation of RGS2 protein expression in astrocyte function is limited. We report the role of ischemic stress in RGS2 protein expression in rat C6 astrocytoma cells and primary mouse astrocytes. A marked increase in RGS2 occurred after ischemic stress induced by chemicals (sodium azide and 2-deoxyglucose) or oxygen-glucose deprivation (OGD, real ischemia). RGS2 mRNA expression was markedly enhanced by 1 h of exposure to chemical ischemia or 6 h of OGD followed by 2 or 6 h of recovery, respectively. This enhanced expression in primary astrocytes and C6 cells was restored to baseline levels after 12 h of recovery from chemically induced ischemic stress or 4–6 h of recovery from OGD. RGS2 protein was also significantly expressed at 12–24 h of recovery from ischemic insult. Ischemia-induced RGS2 upregulation was associated with enhanced apoptosis. It significantly increased annexin V-positive cells, cleaved caspase-3, and enhanced DNA ladder formation and cell cycle arrest. However, a small interfering RNA (siRNA)-mediated RGS2 knockdown reversed the apoptotic cell death associated with ischemia-induced RGS2 upregulation. Upregulated RGS2 was significantly inhibited by SB-203580, a p38 MAPK inhibitor. Rottlerin, a potent inhibitor of PKCδ, completely abrogated the increased RGS2 expression. We also examine whether ischemia-induced RGS2-mediated apoptosis is affected by siRNA-targeted endogenous PKCδ downregulation or its phosphorylation. Although RGS2 upregulation was not affected, siRNA transfection significantly suppressed endogenous PKCδ mRNA and protein expressions. Ischemia-induced PKCδ phosphorylation and caspase-3 cleavage were dose dependently inhibited by PKCδ knockdown, and this endogenous PKCδ suppression reversed ischemia-induced annexin V-positive cells. This study suggests that ischemic stress increases RGS2 expression and that this condition contributes to enhanced apoptosis in C6 cells and primary astrocytes. The signaling it follows may involve PKCδ and p38 MAPK pathways.
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A correlation between RGS2 and oxidative stress was made in a report regarding the postischemic RGS2 upregulation, which leads to enhanced apoptosis in astrocytes via oxygen-glucose deprivation.
“In fact, a correlation between RGS2 and oxidative stress was made in a report regarding the postischemic RGS2 upregulation, which leads to enhanced apoptosis in astrocytes via oxygen-glucose deprivation [243].”
From Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches (2016) · cites this paper as [243]
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Balmus, I. M., Ciobica, A., Antioch, I., Dobrin, R., & Timofte, D. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/3975101 · Cited by 103 · see citing works
“In fact, a correlation between RGS2 and oxidative stress was made in a report regarding the postischemic RGS2 upregulation, which leads to enhanced apoptosis in astrocytes via oxygen-glucose deprivation [243].”
Background
- Authors
- Endale, M., Kim, S. D., Lee, W. M., Kim, S., Suk, K., Cho, J. Y., Park, H. J., Wagley, Y., Kim, S., Oh, J.-W., & Rhee, M. H.
- Affiliations
- Laboratory of Physiology and Signaling, College of Veterinary Medicine, and Brain Science and Engineering Institute, and
- Gyeongsang National University (KR)
- Kyungpook National University (KR)
- Kangwon National University (KR)
- Inje University (KR)
- Konkuk University (KR)
- Corresponding author
- Oh, Jae-Wook
- Rhee, Man Hee
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2010-03
- Volume
- 298
- Issue
- 3
- Pages
- C611-C623
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W2160639308
- Cited by
- 29
- References
- 62
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 1 · 2022: 2 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 6 · 2013: 1 · 2012: 2
- FWCI
- 0.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- RGS2, astrocytes, cerebral ischemia, apoptosis, oxygen-glucose deprivation, p38 MAPK, PKCδ, caspase-3, G protein signaling, siRNA knockdown, SB203580, rottlerin, cell cycle arrest
- MeSH terms
- Animals, Astrocytes, Brain Ischemia, Glucose, Humans, Phosphorylation, Recombinant Fusion Proteins, RNA, Messenger, Time Factors, Transfection, Signal Transduction, Cell Hypoxia, Up-Regulation, Apoptosis, Oxidative Stress, RGS Proteins, RNA Interference, Cell Line, Tumor, Protein Kinase Inhibitors, p38 Mitogen-Activated Protein Kinases, Mice, Rats, Protein Kinase C-delta, Caspase 3
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