Sarco/endoplasmic reticulum Ca²⁺‐ATPase (SERCA2b) mediates oxidation‐induced endoplasmic reticulum stress to regulate neuropathic pain

Abstract

Background and Purpose Neuropathic pain is a widespread health problem with limited curative treatment. Decreased sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA) expression has been reported in dorsal root ganglion (DRG) of animals suffering from neuropathic pain. We aimed to establish the relationship between SERCA expression and the pain responses and to elucidate the underlying molecular mechanism. Experimental Approach Neuropathic pain was modelled using rat chronic constriction injury (CCI). Ca2+ imaging and current clamp patch‐clamp were used to determine cytosolic Ca2+ levels and action potential firing, respectively. Western blots, immunofluorescence staining and qRT‐PCR were used to quantitatively assess protein and mRNA expression, respectively. H&E staining and coupled enzyme assays were used to evaluate the nerve injury and SERCA2b activity, respectively. Key Results SERCA2b is the predominant SERCA isoform in rat DRG and its expression is decreased after CCI at mRNA, protein and activity levels. Whereas inhibiting SERCA with thapsigargin causes neuronal hyperexcitation, nerve injury, endoplasmic reticulum (ER) stress, satellite glial cell activation and mechanical allodynia, activating SERCA by CDN1163 or overexpressing SERCA2b in DRG after CCI produces long‐term relief of mechanical and thermal allodynia accompanied by morphological and functional restoration through alleviation of ER stress. Furthermore, the down‐regulation of DRG SERCA2b in CCI rats is caused by increased production of ROS through Sp1‐dependent transcriptional inhibition. Conclusion and Implications Our findings reveal a novel pathway centring around SERCA2b as the key molecule underlying the mechanism of development and maintenance of neuropathic pain, and SERCA2b activators have the potential for therapeutic treatment of neuropathic pain.

SARS-CoV-2 airway infection results in the development of somatosensory abnormalities in a hamster model

“…Analysis with g:Profiler associated this gene set with neuroplasticity, particularly in the synaptic/dendritic cellular compartments, and strongly associated the transcription factor SP1 (implicated in several pronociceptive mechanisms) with these genes (Fig. 6B) (85)(86)(87). Some of these genes-such as Scn4b (88, 89), Rhobtb2 (90), Mgll (91,92), and Cntfr (93)-have been positively associated with sensory hypersensitivity in response to injury, suggesting that they may be unique mechanisms by which SARS-CoV-2 induces mild hypersensitivity.…”

Restoration of Sarco/Endoplasmic Reticulum Ca2+-ATPase Activity Functions as a Pivotal Therapeutic Target of Anti-Glutamate-Induced Excitotoxicity to Attenuate Endoplasmic Reticulum Ca2+ Depletion

“…Notably, the severity of the ATP2A2 mutant phenotypes parallels the preserved SERCA2 pump activity ( Ahn et al, 2003 ), suggesting that enhancing SERCA2 pump activity and stabilizing ER Ca 2+ storage are vital to the treatment of excitotoxicity-related disorders. For example, in a neuropathic pain model, enhanced SERCA2 expression or activity in dorsal root ganglia neurons alleviated mechanical and thermal abnormalities in pain, and the reduction of ERS was accompanied by morphological and functional recovery ( Li et al, 2022 ). CDN1163 increased ER Ca 2+ content, rescued ERS-induced neuronal death in vitro , and showed significant efficacy in a 6-hydroxydopamine-induced Parkinson’s disease rat model ( Dahl, 2017 ).…”

SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model

“…Interestingly, we identified a group of 53 genes that were upregulated by SARS-CoV-2 at 1dpi but downregulated by SNI (Figure 6A). g:Profiler associated this gene set with neuroplasticity, particularly in the synaptic/dendritic cellular compartments, and strongly associated the Sp1 transcription factor (implicated in several pro-nociceptive mechanisms) with these genes (Figure 6B) (87)(88)(89). Some of these genes, such as Scn4b (90,91), Rhobtb2 (92), Mgll (93,94), and Cntfr (95) have been positively associated with sensory hypersensitivity under injury states, suggesting they may be unique mechanisms by which SARS-CoV-2 induces mild hypersensitivity.…”