nNOS-PSD95 interactions activate the PKC-ε isoform leading to increased GluN1 phosphorylation and the development of neuropathic mechanical allodynia in mice.
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.
['Choi|Sheu-Ran|SR|', 'Han|Ho-Jae|HJ|', 'Beitz|Alvin J|AJ|', 'Lee|Jang-Hern|JH|']
D000818:Animals D000076122:Disks Large Homolog 4 Protein D004789:Enzyme Activation D006930:Hyperalgesia D007527:Isoenzymes D008297:Male D008813:Mice, Inbred ICR D009419:Nerve Tissue Proteins D009437:Neuralgia D052248:Nitric Oxide Synthase Type I D010766:Phosphorylation D010812:Physical Stimulation D051744:Protein Kinase C-epsilon D016194:Receptors, N-Methyl-D-Aspartate D012584:Sciatic Nerve D014110:Touch
GluN1 Phosphorylation Mechanical allodynia Neuronal nitric oxide synthase Postsynaptic density 95 Protein kinase C