Sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA2b) mediates oxidation‐induced endoplasmic reticulum stress to regulate neuropathic pain. (13th January 2022)

• Record Type: Journal Article
• Authors: Li, Shaoheng; Zhao, Fang; Tang, Qinglian; Xi, Chuchu; He, Jing; Wang, Yujing; Zhu, Michael X.; Cao, Zhengyu
• Other Names: Mauro Claudio guestEditor.; Naylor Amy guestEditor.; Lord Janet M. guestEditor.
• Is Part Of: British journal of pharmacology. Volume 179:Number 9(2022)
• Page Start: 2016
• Page End: 2036
• Publication Date: 2022-01-13
• Subjects: ER stress -- neuropathic pain -- oxidative stress -- SERCA2b; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.15744
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : Background and Purpose: Neuropathic pain is a widespread health problem with limited curative treatment. Decreased sarco/endoplasmic reticulum Ca 2+ ‐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). Ca 2+ imaging and current clamp patch‐clamp were used to determine cytosolic Ca 2+ 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. Abstract : Sciatic nerve ligation‐induced oxidative stress reduces SERCA2b expression in dorsal root ganglions by up‐regulation of Sp1 transcription. Reduced SERCA2b expression causes endoplasmic reticulum stress that leads to nerve injury and hyperexcitation of dorsal root ganglion neurons. Overexpression or pharmacological activation of SERCA2b induce persistent alleviation of neuropathic pain in sciatic nerve ligation rat model through mitigation of endoplasmic reticulum stress, indicating that SERCA2b is a potential molecular target to discover the treatment of neuropathic pain.