title: Redox-guided axonal regrowth requires cyclic GMP dependent protein kinase 1: Implication for neuropathic pain.
abstract: 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.
authors.affiliation: Depts. of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Lucie
authors.initials: L
authors.lastname: Valek
authors.affiliation: Depts. of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.affiliation: Depts. of Anaesthesiology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dröse
authors.affiliation: King's College of London, Cardiovascular Division, The Rayne Institute, St. Thomas' Hospital, London, United Kingdom.
authors.forename: Philipp
authors.initials: P
authors.lastname: Eaton
authors.affiliation: Depts. of Cardiovascular Physiology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
authors.affiliation: Depts. of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany. Electronic address: itegeder@hotmail.com.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D006152:Cyclic GMP / Q000235:genetics; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017774:Long-Term Potentiation / Q000235:genetics; D051379:Mice; D009437:Neuralgia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D015398:Signal Transduction
chemical_list: D062965:Cyclic GMP-Dependent Protein Kinase Type I; D006152:Cyclic GMP
keywords: Cofilin; Growth cone; Nerve regeneration; Pain; Redox; Sensory neuron; Signaling ROS