title: Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity.
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.
authors: Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, Minnesota, USA; Department of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rochester, Minnesota, USA.
authors: Hyesook
authors: H
authors: Yoon
authors: Maja
authors: M
authors: Radulovic
authors: Jianmin
authors: J
authors: Wu
authors: Sachiko I
authors: SI
authors: Blaber
authors: Michael
authors: M
authors: Blaber
authors: Michael G
authors: MG
authors: Fehlings
authors: Isobel A
authors: IA
authors: Scarisbrick
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D005260:Female; D018698:Glutamic Acid / Q000633:toxicity*; D007610:Kallikreins / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000502:physiology; D009474:Neurons / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000503:physiopathology*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D044463:Receptor, PAR-1 / Q000235:genetics / Q000502:physiology*; D044464:Receptor, PAR-2 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology; D013119:Spinal Cord Injuries / Q000473:pathology; D013917:Thrombin / Q000235:genetics / Q000502:physiology
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018698:Glutamic Acid; D012313:RNA; D007610:Kallikreins; C491223:Prss18 protein, mouse; D013917:Thrombin
keywords: axon; neurodegeneration; spinal cord injury; thrombin; trauma
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