ArticleJournal of neurochemistry2013
Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity.
Article in Journal of neurochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 60 citations in OpenAlex.
- Herpes simplex virus and kallikrein-related peptidases - a functional connection in Alzheimer's disease.Alzheimer's research & therapy · 2026Article
- KLK6 regulates ferroptosis through YAP/TAZ in lung adenocarcinoma.Translational cancer research · 2026Article
- Drug Discovery Strategies for Kallikrein-Related Peptidases.International journal of molecular sciences · 2025Review
- Multiomics approach identifies SERPINB1 as candidate biomarker for spinocerebellar ataxia type 2.Scientific reports · 2025Article
- High-Throughput Activity Reprogramming of Proteases (HARP).ACS chemical biology · 2025Article
- Exerkine irisin mitigates cognitive impairment by suppressing gut-brain axis-mediated inflammation.Journal of advanced research · 2025Article
- A New Strategy in Modulating the Protease-Activated Receptor 2 (Par2) in Autoimmune Diseases.International journal of molecular sciences · 2025Review
- Before, during, and after: An Argument for Safety and Improved Outcome of Thrombolysis in Acute Ischemic Stroke with Direct Oral Anticoagulant Treatment.Annals of neurology · 2024Review
- Which neuroimaging and fluid biomarkers method is better in theranostic of Alzheimer's disease? An umbrella review.IBRO neuroscience reports · 2024Review
- PARting Neuroinflammation with Protease-Activated Receptor 2 Pepducins.The Journal of pharmacology and experimental therapeutics · 2024Article
- Systemic Inflammation Leads to Changes in the Intracellular Localization of KLK6 in Oligodendrocytes in Spinal Cord White Matter.Neurochemical research · 2023Article
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- Thrombin induces morphological and inflammatory astrocytic responses via activation of PAR1 receptor.Cell death discovery · 2022Article
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- Nafamostat mesylate attenuates the pathophysiologic sequelae of neurovascular ischemia.Neural regeneration research · 2020Review
- Protein Degradome of Spinal Cord Injury: Biomarkers and Potential Therapeutic Targets.Molecular neurobiology · 2020Review
- Involvement of Kallikrein-Related Peptidases in Nervous System Disorders.Frontiers in cellular neuroscience · 2020Article
- Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases.Thrombosis journal · 2019Review
- Roles of Coagulation Proteases and PARs (Protease-Activated Receptors) in Mouse Models of Inflammatory Diseases.Arteriosclerosis, thrombosis, and vascular biology · 2019Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
CNS trauma generates a proteolytic imbalance contributing to secondary injury, including axonopathy and neuron degeneration. Kallikrein 6 (Klk6) is a serine protease implicated in neurodegeneration, and here we investigate the role of protease-activated receptors 1 (PAR1) and PAR2 in mediating these effects. First, we demonstrate Klk6 and the prototypical activator of PAR1, thrombin, as well as PAR1 and PAR2, are each elevated in murine experimental traumatic spinal cord injury (SCI) at acute or subacute time points. Recombinant Klk6 triggered extracellular signal-regulated kinase (ERK1/2) signaling in cerebellar granule neurons and in the NSC34 spinal cord motoneuron cell line, in a phosphoinositide 3-kinae and MEK-dependent fashion. Importantly, lipopeptide inhibitors of PAR1 or PAR2, and PAR1 genetic deletion, each reduced Klk6-ERK1/2 activation. In addition, Klk6 and thrombin promoted degeneration of cerebellar neurons and exacerbated glutamate neurotoxicity. Moreover, genetic deletion of PAR1 blocked thrombin-mediated cerebellar neurotoxicity and reduced the neurotoxic effects of Klk6. Klk6 also increased glutamate-mediated Bim signaling, poly-ADP-ribose polymerase cleavage and lactate dehydrogenase release in NSC34 motoneurons and these effects were blocked by PAR1 and PAR2 lipopeptide inhibitors. Taken together, these data point to a novel Klk6-signaling axis in CNS neurons that is mediated by PAR1 and PAR2 and is positioned to contribute to neurodegeneration.
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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.