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Kallikrein 6 Signals through PAR1 and PAR2 to Promote Neuron Injury and Exacerbate Glutamate Neurotoxicity

Title: Kallikrein 6 Signals through PAR1 and PAR2 to Promote Neuron Injury and Exacerbate Glutamate Neurotoxicity.
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Name(s): Yoon, Hyesook, author
Radulovic, Maja, author
Wu, Jianmin, author
Blaber, Sachiko, author
Blaber, Michael, author
Fehlings, Michael, author
Scarisbrick, Isobel, author
Type of Resource: text
Genre: text
Date Issued: 2013-11-01
Physical Form: computer
Physical Form: online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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 ERK1/2 signaling in cerebellar granule neurons and in the NSC34 spinal cord motoneuron cell line, in a PI3K 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, PARP cleavage and lactate dehydrogenase (LDH) 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.
Identifier: FSU_libsubv1_scholarship_submission_1464450461 (IID), 10.1111/jnc.12293 (DOI)
Keywords: Spinal cord injury, Thrombin, Axon, Neurodegeneration, Trauma
Publication Note: Publisher's Version available at http://onlinelibrary.wiley.com/doi/10.1111/jnc.12293/full
Preferred Citation: Yoon, H. Radulovic, M. Wu, J. Blaber, S. Blaber, M. Fehlings, M. Scarisbrick, I. (2001). Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity. Journal of Neurochemistry. 127 (2). 289-298
Grant Number: R01NS052741
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_libsubv1_scholarship_submission_1464450461
Owner Institution: FSU
Is Part Of: Journal of Neurochemistry.
Issue: iss. 2, vol. 127