Spinal serum-inducible and glucocorticoid-inducible kinase 1 mediates neuropathic pain via kalirin and downstream PSD-95-dependent NR2B phosphorylation in rats

Hsien Yu Peng, Gin Den Chen, Cheng Yuan Lai, Ming Chun Hsieh, Tzer-Bin Lin

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Abstract

The coupling of the spinal postsynaptic density-95 (PSD-95) with the glutamatergic N-methyl-D-aspartate receptor NR2B subunit and the subsequent NR2B phosphorylation contribute to pain-related plasticity. Increasing evidence reveals that kalirin, a Rho-guanine nucleotide exchange factor, modulates PSD-95-NR2B-dependent neuroplasticity. Our laboratory recently demonstrated that serum-inducible and glucocorticoid-inducible kinase 1 (SGK1) participates in inflammation-associated pain hypersensitivity by modulating spinal glutamatergic neurotransmission. Because kalirin is one of the proteinsin PSD that is highly phosphorylated by various kinases, we tested whether kalirin could be a downstream target of spinal SGK1 that participates in neuropathic pain development via regulation of the PSD-95-NR2B coupling dependent phosphorylation of NR2B. We observed that spinal nerve ligation (SNL, L5) in male Sprague Dawley rats resulted in behavioral allodynia, which was associated with phosphorylated SGK1 (pSGK1), kalirin, and phosphorylatedNR2B(pNR2B) expression and an increase in pSGK1-kalirin-PSD-95-pNR2B coprecipitation in the ipsilateral dorsal horn (L4-L5). SNL-enhanced kalirin immunofluorescence was coincidentwithpSGK1, PSD-95, and p NR2 Bimmunoreactivity. Small-interfering RNA (siRNA) that targetedspinal kalirinm RNA expression (10μg, 10μl; i.t.) reduced SNL-induced allodynia, kalirin and pNR2B expression, as well as kalirin-PSD-95 and PSD-95-pNR2B coupling and costaining without affecting SGK1 phosphorylation. Daily administration of GSK-650394 (an SGK1 antagonist; 100 nM, 10μl, i.t.) not only exhibited effects similar to the kalirin mRNA-targeting siRNA but also attenuatedpSGK1-kalirin costaining and SGK1-kalirin coupling. Wesuggest that nerve injury could induce spinal SGK1 phosphorylation that subsequently interacts with and upregulates kalirin to participate in neuropathic pain development via PSD-95-NR2B coupling-dependent NR2B phosphorylation.

Original languageEnglish
Pages (from-to)5227-5240
Number of pages14
JournalJournal of Neuroscience
Volume33
Issue number12
DOIs
Publication statusPublished - Mar 20 2013

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Post-Synaptic Density
Neuralgia
Glucocorticoids
Phosphotransferases
Phosphorylation
Serum
Hyperalgesia
Small Interfering RNA
Rho Guanine Nucleotide Exchange Factors
Pain
Spinal Nerves
Neuronal Plasticity
Synaptic Transmission
Fluorescent Antibody Technique
Ligation
Sprague Dawley Rats
Hypersensitivity
Up-Regulation
RNA
Inflammation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Spinal serum-inducible and glucocorticoid-inducible kinase 1 mediates neuropathic pain via kalirin and downstream PSD-95-dependent NR2B phosphorylation in rats. / Peng, Hsien Yu; Chen, Gin Den; Lai, Cheng Yuan; Hsieh, Ming Chun; Lin, Tzer-Bin.

In: Journal of Neuroscience, Vol. 33, No. 12, 20.03.2013, p. 5227-5240.

Research output: Contribution to journalArticle

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abstract = "The coupling of the spinal postsynaptic density-95 (PSD-95) with the glutamatergic N-methyl-D-aspartate receptor NR2B subunit and the subsequent NR2B phosphorylation contribute to pain-related plasticity. Increasing evidence reveals that kalirin, a Rho-guanine nucleotide exchange factor, modulates PSD-95-NR2B-dependent neuroplasticity. Our laboratory recently demonstrated that serum-inducible and glucocorticoid-inducible kinase 1 (SGK1) participates in inflammation-associated pain hypersensitivity by modulating spinal glutamatergic neurotransmission. Because kalirin is one of the proteinsin PSD that is highly phosphorylated by various kinases, we tested whether kalirin could be a downstream target of spinal SGK1 that participates in neuropathic pain development via regulation of the PSD-95-NR2B coupling dependent phosphorylation of NR2B. We observed that spinal nerve ligation (SNL, L5) in male Sprague Dawley rats resulted in behavioral allodynia, which was associated with phosphorylated SGK1 (pSGK1), kalirin, and phosphorylatedNR2B(pNR2B) expression and an increase in pSGK1-kalirin-PSD-95-pNR2B coprecipitation in the ipsilateral dorsal horn (L4-L5). SNL-enhanced kalirin immunofluorescence was coincidentwithpSGK1, PSD-95, and p NR2 Bimmunoreactivity. Small-interfering RNA (siRNA) that targetedspinal kalirinm RNA expression (10μg, 10μl; i.t.) reduced SNL-induced allodynia, kalirin and pNR2B expression, as well as kalirin-PSD-95 and PSD-95-pNR2B coupling and costaining without affecting SGK1 phosphorylation. Daily administration of GSK-650394 (an SGK1 antagonist; 100 nM, 10μl, i.t.) not only exhibited effects similar to the kalirin mRNA-targeting siRNA but also attenuatedpSGK1-kalirin costaining and SGK1-kalirin coupling. Wesuggest that nerve injury could induce spinal SGK1 phosphorylation that subsequently interacts with and upregulates kalirin to participate in neuropathic pain development via PSD-95-NR2B coupling-dependent NR2B phosphorylation.",
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