ArticleProceedings of the National Academy of Sciences of the United States of America2013
Phospholipase C epsilon links G protein-coupled receptor activation to inflammatory astrocytic responses.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.
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Who cites it
64 citing papers in PubMed, 1 synthesis or guideline pooled it, 83 citations in OpenAlex.
- Genome-wide association susceptibility loci for cluster headache support a role for inflammation in the pathophysiology.The journal of headache and pain · 2026Pooled it
- Phospholipases: Where Do We Stand?Methods in molecular biology (Clifton, N.J.) · 2027Review
- Structural insights into Phospholipase Cε activity and regulation.The Journal of biological chemistry · 2026Review
- From lipid function to dysfunction: Very long-chain fatty acids as emerging regulators of neuroinflammatory pathways.iScience · 2026Review
- Increase of intracellular ZnScientific reports · 2025Article
- Phospholipase C epsilon 1 as a therapeutic target in cardiovascular diseases.Journal of advanced research · 2025Review
- RhoA allosterically activates phospholipase Cε via its EF hands.Communications biology · 2025Article
- Astrocytic ET-1 System Determines Microglia Phenotype Following Spinal Cord Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Untangling the role of RhoA in the heart: protective effect and mechanism.Cell death & disease · 2024Review
- GRespiratory research · 2024Review
- GPCR-Gα13 Involvement in Mitochondrial Function, Oxidative Stress, and Prostate Cancer.International journal of molecular sciences · 2024Review
- Phospholipase C epsilon-1 (PLCƐ1) mediates macrophage activation and protection against tuberculosis.Infection and immunity · 2024Article
- Thrombin increases the expression of cholesterol 25-hydroxylase in rat astrocytes after spinal cord injury.Neural regeneration research · 2023Article
- Activation Mechanisms and Diverse Functions of Mammalian Phospholipase C.Biomolecules · 2023Review
- Astrocytic MicroRNAs and Transcription Factors in Alzheimer's Disease and Therapeutic Interventions.Cells · 2022Review
- Phospholipase Cε insufficiency causes ascending aortic aneurysm and dissection.American journal of physiology. Heart and circulatory physiology · 2022Article
- Identification of hub genes in the subacute spinal cord injury in rats.BMC neuroscience · 2022Article
- Lactate receptor HCAR1 regulates cell growth, metastasis and maintenance of cancer‑specific energy metabolism in breast cancer cells.Molecular medicine reports · 2022Article
- Thrombin acts as inducer of proinflammatory macrophage migration inhibitory factor in astrocytes following rat spinal cord injury.Journal of neuroinflammation · 2022Article
- Thrombin induces morphological and inflammatory astrocytic responses via activation of PAR1 receptor.Cell death discovery · 2022Article
4 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Neuroinflammation plays a major role in the pathophysiology of diseases of the central nervous system, and the role of astroglial cells in this process is increasingly recognized. Thrombin and the lysophospholipids lysophosphatidic acid and sphingosine 1-phosphate (S1P) are generated during injury and can activate G protein-coupled receptors (GPCRs) on astrocytes. We postulated that GPCRs that couple to Ras homolog gene family, member A (RhoA) induce inflammatory gene expression in astrocytes through the small GTPase responsive phospholipase Cε (PLCε). Using primary astrocytes from wild-type and PLCε knockout mice, we demonstrate that 1-h treatment with thrombin or S1P increases cyclooxygenase 2 (COX-2) mRNA levels ∼10-fold and that this requires PLCε. Interleukin-6 and interleukin-1β mRNA levels are also increased in a PLCε-dependent manner. Thrombin, lysophosphatidic acid, and S1P increase COX-2 protein expression through a mechanism involving RhoA, catalytically active PLCε, sustained activation of protein kinase D (PKD), and nuclear translocation of NF-κB. Endogenous ligands that are released from astrocytes in an in vitro wounding assay also induce COX-2 expression through a PLCε- and NF-κB-dependent pathway. Additionally, in vivo stab wound injury activates PKD and induces COX-2 and other inflammatory genes in WT but not in PLCε knockout mouse brain. Thus, PLCε links GPCRs to sustained PKD activation, providing a means for GPCR ligands that couple to RhoA to induce NF-κB signaling and promote neuroinflammation.
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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.