ArticlePloS one2012
Granzyme B-induced neurotoxicity is mediated via activation of PAR-1 receptor and Kv1.3 channel.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
32 citing papers in PubMed, 54 citations in OpenAlex.
- Serum Granzyme B in Parkinson's Disease: A Case-Control Study of Diagnostic Association.Journal of clinical medicine · 2026Article
- Emerging roles of granzymes in neurodegeneration and neuroinflammation: mechanistic insights and therapeutic opportunities.Acta neuropathologica · 2026Review
- Decoding the human PBMC isonome: isoform-level resolution with single-cell long-read transcriptomics.Frontiers in genetics · 2026Article
- Granzyme B contributes to subretinal fibrosis in neovascular age-related macular degeneration by modulating inflammation and epithelial-mesenchymal transition.Journal of neuroinflammation · 2025Article
- Decoding the human PBMC isonome: Isoform-level resolution with single-cell long-read transcriptomics.bioRxiv : the preprint server for biology · 2025Article
- Angiogenic CD8 T cells from PWH induce Granzymes-dependent PAR1 activation promoting endothelial inflammation.bioRxiv : the preprint server for biology · 2025Article
- Pathotype-Specific Expression of Granzyme-Perforin Pathway Genes and Their Association With Clinical Disease Activity in Early Rheumatoid Arthritis and in a Randomized Clinical Trial.Immune network · 2025Article
- Diverse cell types establish a pathogenic immune environment in peripheral neuropathy.Journal of neuroinflammation · 2025Article
- Activity of Potassium Channels in CD8International journal of molecular sciences · 2024Article
- Reassessing granzyme B: unveiling perforin-independent versatility in immune responses and therapeutic potentials.Frontiers in immunology · 2024Review
- The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Distinct Cellular Tropism and Immune Responses to Alphavirus Infection.Annual review of immunology · 2022Review
- Granzyme K initiates IL-6 and IL-8 release from epithelial cells by activating protease-activated receptor 2.PloS one · 2022Article
- The role of protease-activated receptor 1 signaling in CD8 T cell effector functions.iScience · 2021Article
- Protease Activated Receptor 1 and Its Ligands as Main Regulators of the Regeneration of Peripheral Nerves.Biomolecules · 2021Review
- Involvement of cytotoxic Eomes-expressing CD4Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Protease-Activated Receptor 1 Deletion Causes Enhanced Osteoclastogenesis in Response to Inflammatory Signals through a Notch2-Dependent Mechanism.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases.Thrombosis journal · 2019Review
- Human Granzyme B Based Targeted Cytolytic Fusion Proteins.Biomedicines · 2018Review
- Silent Free Fall at Disease Onset: A Perspective on Therapeutics for Progressive Multiple Sclerosis.Frontiers in neurology · 2018Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
Increasing evidence supports a critical role of T cells in neurodegeneration associated with acute and subacute brain inflammatory disorders. Granzyme B (GrB), released by activated T cells, is a cytotoxic proteinase which may induce perforin-independent neurotoxicity. Here, we studied the mechanism of perforin-independent GrB toxicity by treating primary cultured human neuronal cells with recombinant GrB. GrBactivated the protease-activated receptor (PAR)-1 receptor on the neuronal cell surface leading to decreased intracellular cyclic AMP levels. This was followed by increased expression and translocation of the voltage gated potassium channel, Kv1.3 to the neuronal cell membrane. Similar expression of Kv1.3 was also seen in neurons of the cerebral cortex adjacent to active inflammatory lesions in patients with multiple sclerosis. Kv1.3 expression was followed by activation of Notch-1 resulting in neurotoxicity. Blocking PAR-1, Kv1.3 or Notch-1 activation using specific pharmacological inhibitors or siRNAs prevented GrB-induced neurotoxicity. Furthermore, clofazimine protected against GrB-induced neurotoxicity in rat hippocampus, in vivo. These observations indicate that GrB released from T cells induced neurotoxicity by interacting with the membrane bound Gi-coupled PAR-1 receptor and subsequently activated Kv1.3 and Notch-1. These pathways provide novel targets to treat T cell-mediated neuroinflammatory disorders. Kv1.3 is of particular interest since it is expressed on the cell surface, only under pathological circumstances, and early in the cascade of events making it an attractive therapeutic target.
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What OpenQuestion holds
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.