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.

Barbamide Displays Affinity for Membrane-Bound Receptors and Impacts Store-Operated Calcium Entry in Mouse Sensory Neurons

“…Such a reduction in KCl depolarization fits with our observations. However, the notion that sigma-1 affects sensory neurons primarily through the modulation of voltage-gated Ca 2+ channels does not fit as well with our observed effects of barbamide on SOCE [ 23 ].…”

Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine

“… Schematic illustration of the model of the signaling mechanism. SIGMAR1/Sigma-1 receptor translocates from the endoplasmic reticulum (ER) to nuclear membrane when cells are under stressful conditions [ 83 ]. ( A ) When motor neurons are under the insult of toxic (G4C2)RNA repeats upon their nuclear pore proteins [ 13 ], POM121 cannot recruit KPNB1/importinβ1 for the nuclear import of transcription factor TFEB.…”

SIGMAR1 Confers Innate Resilience against Neurodegeneration

“…This response seems to be enhanced in transgenic mice with overexpressed 4E-BP1, which is part of the mTOR pathway and therefore plays a fundamental role in the control of pro-survival gene transcription [25]. Wang et al observed that the knock-out of SIGMAR1 in human embryonic kidney 293T cells decreased the expression of 4E-BP1, which suggests that SIGMAR1 does not only affect UPR from the ER but also from the mitochondria, since 4E-BP1 can impact UPRm [26]. Finally, Mori et al observed that, like SIGMAR1, IRE1 is enriched at the MAM in Chinese hamster ovarian cells.…”

“…Figure1. Innate resilience provided by SIGMAR1 from head to tail against neurodegeneration[4,22,26,39,47,48,52,61,62,64,66,[68][69][70][71][72]75,78].…”