nNOS-PSD95 interactions activate the PKC-ε isoform leading to increased GluN1 phosphorylation and the development of neuropathic mechanical allodynia in mice.

Abstract

It has been suggested that interactions of neuronal nitric oxide synthase (nNOS) with postsynaptic density 95 (PSD95) play important roles in the development of chronic neuropathic pain. Here we examine the possible role of nNOS-PSD95 interactions in central sensitization as represented by phosphorylation of the NMDA receptor GluN1 subunit (pGluN1) in mice with chronic constriction injury (CCI) of the sciatic nerve. Intrathecal administration of the nNOS-PSD95 interactions inhibitor, IC87201 on post-operative days 0-3 significantly reduced the CCI-induced increase in total NO levels in the lumbar spinal cord dorsal horn. IC87201 administration on post-operative days 0-3 also attenuated the CCI-induced development of mechanical allodynia (MA) and PKC-dependent (Ser896) pGluN1. Sciatic nerve injury elicited a significant translocation of the PKC-ε isoform from the cytosol to the membrane fraction in the lumbar spinal cord dorsal horn on day 3 post-CCI surgery. Administration of IC87201 significantly inhibited this translocation of PKC-ε, while the expression of PKC-α and -ξ in the cytosol and membrane fractions was unaffected by sciatic nerve injury or injection of IC87201. Furthermore, administration of the PKC-ε inhibitor, εV1-2 on post-operative days 0-3 attenuated the CCI-induced development of MA and pGluN1. Collectively these results demonstrate that spinal nNOS-PSD95 interactions play an important role in PKC-dependent GluN1 phosphorylation via activation of the PKC-ε isoform, and ultimately contributes to the development of MA in peripheral neuropathy.

• Authors: Sheu-Ran Choi, Ho-Jae Han, Alvin J Beitz, Jang-Hern Lee
• Journal: Neuroscience letters (Neurosci Lett) Vol. 703 Pg. 156-161 (06 11 2019) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 30926374 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Disks Large Homolog 4 Protein
• Dlg4 protein, mouse
• Gprin1 protein, mouse
• Isoenzymes
• Nerve Tissue Proteins
• Receptors, N-Methyl-D-Aspartate
• Nitric Oxide Synthase Type I
• Nos1 protein, mouse
• Protein Kinase C-epsilon

Topics

• Animals
• Disks Large Homolog 4 Protein (metabolism)
• Enzyme Activation
• Hyperalgesia (metabolism)
• Isoenzymes (metabolism)
• Male
• Mice, Inbred ICR
• Nerve Tissue Proteins (metabolism)
• Neuralgia (metabolism)
• Nitric Oxide Synthase Type I (metabolism)
• Phosphorylation
• Physical Stimulation
• Protein Kinase C-epsilon (metabolism)
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Sciatic Nerve (injuries)
• Touch