Genomic Action of Sigma-1 Receptor Chaperone Relates to Neuropathic Pain

Shao Ming Wang, Nino Goguadze, Yuriko Kimura, Yuko Yasui, Bin Pan, Tzu Yun Wang, Yoki Nakamura, Yu Ting Lin, Quinn H. Hogan, Katherine L. Wilson, Tsung Ping Su, Hsiang en Wu

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER) chaperones implicated in neuropathic pain. Here we examine if the Sig-1R may relate to neuropathic pain at the level of dorsal root ganglia (DRG). We focus on the neuronal excitability of DRG in a “spare nerve injury” (SNI) model of neuropathic pain in rats and find that Sig-1Rs likely contribute to the genesis of DRG neuronal excitability by decreasing the protein level of voltage-gated Cav2.2 as a translational inhibitor of mRNA. Specifically, during SNI, Sig-1Rs translocate from ER to the nuclear envelope via a trafficking protein Sec61β. At the nucleus, the Sig-1R interacts with cFos and binds to the promoter of 4E-BP1, leading to an upregulation of 4E-BP1 that binds and prevents eIF4E from initiating the mRNA translation for Cav2.2. Interestingly, in Sig-1R knockout HEK cells, Cav2.2 is upregulated. In accordance with those findings, we find that intra-DRG injection of Sig-1R agonist (+)pentazocine increases frequency of action potentials via regulation of voltage-gated Ca2+ channels. Conversely, intra-DRG injection of Sig-1R antagonist BD1047 attenuates neuropathic pain. Hence, we discover that the Sig-1R chaperone causes neuropathic pain indirectly as a translational inhibitor.

Original languageEnglish (US)
Pages (from-to)2523-2541
Number of pages19
JournalMolecular Neurobiology
Volume58
Issue number6
DOIs
StatePublished - Jun 2021
Externally publishedYes

Keywords

  • 4E-BP1
  • Dorsal root ganglia
  • Neuropathic pain
  • Sigma-1 receptor
  • Spare nerve injury
  • Translational inhibition

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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