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

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.

• Authors: 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
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 58 Issue 6 Pg. 2523-2541 (Jun 2021) ISSN: 1559-1182 [Electronic] United States
• PMID: 33459966 (Publication Type: Journal Article)

Chemical References

• Cacna1b protein, rat
• Calcium Channels, N-Type
• Eif4ebp1 protein, rat
• Eukaryotic Initiation Factor-4E
• Intracellular Signaling Peptides and Proteins
• Proto-Oncogene Proteins c-fos
• RNA Caps
• RNA, Messenger
• Receptors, sigma
• SEC Translocation Channels

Topics

• Animals
• Calcium Channels, N-Type (genetics, metabolism)
• Endoplasmic Reticulum (metabolism)
• Eukaryotic Initiation Factor-4E (metabolism)
• Ganglia, Spinal (metabolism)
• Gene Expression Regulation
• Genome
• HEK293 Cells
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Nerve Tissue (injuries, pathology)
• Neuralgia (genetics)
• Nuclear Envelope (metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Biosynthesis
• Proto-Oncogene Proteins c-fos (metabolism)
• RNA Caps (metabolism)
• RNA, Messenger (genetics, metabolism)
• Rats, Sprague-Dawley
• Receptors, sigma (agonists, genetics, metabolism)
• SEC Translocation Channels (metabolism)
• Transcription, Genetic
• Sigma-1 Receptor
• Rats