Genomic Action of Sigma-1 Receptor Chaperone Relates to Neuropathic Pain. Mol Neurobiol 2021 Jun;58(6):2523-2541
Date
01/19/2021Pubmed ID
33459966Pubmed Central ID
PMC8128747DOI
10.1007/s12035-020-02276-8Scopus ID
2-s2.0-85100181606 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
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.
Author List
Wang SM, Goguadze N, Kimura Y, Yasui Y, Pan B, Wang TY, Nakamura Y, Lin YT, Hogan QH, Wilson KL, Su TP, Wu HEAuthor
Quinn H. Hogan MD Professor in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCalcium Channels, N-Type
Endoplasmic Reticulum
Eukaryotic Initiation Factor-4E
Ganglia, Spinal
Gene Expression Regulation
Genome
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins
Male
Nerve Tissue
Neuralgia
Nuclear Envelope
Promoter Regions, Genetic
Protein Biosynthesis
Proto-Oncogene Proteins c-fos
RNA Caps
RNA, Messenger
Rats
Rats, Sprague-Dawley
Receptors, sigma
SEC Translocation Channels
Transcription, Genetic
