Blocking the Spinal Fbxo3/CARM1/K+ Channel Epigenetic Silencing Pathway as a Strategy for Neuropathic Pain Relief

Ming Chun Hsieh, Yu Cheng Ho, Cheng Yuan Lai, Hsueh Hsiao Wang, Po Sheng Yang, Jen Kun Cheng, Gin Den Chen, Soo Cheen Ng, An Sheng Lee, Kuang Wen Tseng, Tzer Bin Lin, Hsien Yu Peng

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Many epigenetic regulators are involved in pain-associated spinal plasticity. Coactivator-associated arginine methyltransferase 1 (CARM1), an epigenetic regulator of histone arginine methylation, is a highly interesting target in neuroplasticity. However, its potential contribution to spinal plasticity–associated neuropathic pain development remains poorly explored. Here, we report that nerve injury decreased the expression of spinal CARM1 and induced allodynia. Moreover, decreasing spinal CARM1 expression by Fbxo3-mediated CARM1 ubiquitination promoted H3R17me2 decrement at the K+ channel promoter, thereby causing K+ channel epigenetic silencing and the development of neuropathic pain. Remarkably, in naïve rats, decreasing spinal CARM1 using CARM1 siRNA or a CARM1 inhibitor resulted in similar epigenetic signaling and allodynia. Furthermore, intrathecal administration of BC-1215 (a novel Fbxo3 inhibitor) prevented CARM1 ubiquitination to block K+ channel gene silencing and ameliorate allodynia after nerve injury. Collectively, the results reveal that this newly identified spinal Fbxo3-CARM1-K+ channel gene functional axis promotes neuropathic pain. These findings provide essential insights that will aid in the development of more efficient and specific therapies against neuropathic pain.

Original languageEnglish
Pages (from-to)1295-1315
Number of pages21
JournalNeurotherapeutics
Volume18
Issue number2
DOIs
Publication statusPublished - Apr 2021

Keywords

  • CARM1
  • Fbxo3
  • Histone arginine methylation
  • neuropathic pain
  • spinal

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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