Redox-guided axonal regrowth requires cyclic GMP dependent protein kinase 1 : implication for neuropathic pain

  • Cyclic GMP-dependent protein kinase 1 (PKG1) mediates presynaptic nociceptive long-term potentiation (LTP) in the spinal cord and contributes to inflammatory pain in rodents but the present study revealed opposite effects in the context of neuropathic pain. We used a set of loss-of-function models for in vivo and in vitro studies to address this controversy: peripheral neuron specific deletion (SNS-PKG1-/-), inducible deletion in subsets of neurons (SLICK-PKG1-/-) and redox-dead PKG1 mutants. In contrast to inflammatory pain, SNS-PKG1-/- mice developed stronger neuropathic hyperalgesia associated with an impairment of nerve regeneration, suggesting specific repair functions of PKG1. Although PKG1 accumulated at the site of injury, its activity was lost in the proximal nerve due to a reduction of oxidation-dependent dimerization, which was a consequence of mitochondrial damage in injured axons. In vitro, PKG1 deficiency or its redox-insensitivity resulted in enhanced outgrowth and reduction of growth cone collapse in response to redox signals, which presented as oxidative hotspots in growing cones. At the molecular level, PKG1 deficiency caused a depletion of phosphorylated cofilin, which is essential for growth cone collapse and guidance. Hence, redox-mediated guidance required PKG1 and consequently, its deficiency in vivo resulted in defective repair and enhanced neuropathic pain after nerve injury. PKG1-dependent repair functions will outweigh its signaling functions in spinal nociceptive LTP, so that inhibition of PKG1 is no option for neuropathic pain.

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Author:Lucie ValekORCiDGND, Annett Häussler, Stefan DröseORCiDGND, Philipp Eaton, Katrin SchröderORCiDGND, Irmgard TegederORCiDGND
URN:urn:nbn:de:hebis:30:3-432433
DOI:https://doi.org/10.1016/j.redox.2016.12.004
ISSN:2213-2317
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/27978504
Parent Title (German):Redox Biology
Publisher:Elsevier
Place of publication:Amsterdam [u. a.]
Document Type:Article
Language:English
Date of Publication (online):2017/06/29
Year of first Publication:2016
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/06/29
Tag:Cofilin; Growth cone; Nerve regeneration; Pain; Redox; Sensory neuron; Signaling ROS
Volume:11
Page Number:16
First Page:176
Last Page:191
Note:
© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
HeBIS-PPN:425339580
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0