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Monitoring ER/SR Calcium Release with the Targeted Ca2+ Sensor CatchER+
Published on: May 19, 2017
Sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA2b) mediates oxidation-induced endoplasmic reticulum stress to
Shaoheng Li1, Fang Zhao1, Qinglian Tang1
1State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
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.
Insights
Decreased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) in neuropathic pain is linked to neuronal hyperexcitation. Activating SERCA2b offers therapeutic potential for pain relief by alleviating endoplasmic reticulum stress.
Area of Science:
- Neuroscience
- Molecular Biology
- Pain Research
Background:
- Neuropathic pain is a prevalent condition with limited effective treatments.
- Reduced sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) expression in dorsal root ganglion (DRG) is observed in neuropathic pain models.
- The precise role of SERCA in neuropathic pain mechanisms requires further elucidation.
Purpose of the Study:
- To investigate the relationship between SERCA expression and pain responses in neuropathic pain.
- To elucidate the molecular mechanisms underlying SERCA's involvement in neuropathic pain.
- To explore the therapeutic potential of targeting SERCA for neuropathic pain treatment.
Main Methods:
- Neuropathic pain was induced using the chronic constriction injury (CCI) model in rats.
- Assessed cytosolic Ca2+ levels and neuronal firing using Ca2+ imaging and patch-clamp techniques.
- Quantified SERCA expression and activity using Western blot, immunofluorescence, qRT-PCR, and enzyme assays.
Main Results:
- SERCA2b, the primary SERCA isoform in rat DRG, showed decreased expression (mRNA, protein, activity) post-CCI.
- Inhibition of SERCA induced neuronal hyperexcitation, ER stress, and allodynia.
- Activation of SERCA2b via CDN1163 or overexpression provided long-term relief from allodynia by reducing ER stress.
- Down-regulation of DRG SERCA2b in CCI rats resulted from increased reactive oxygen species (ROS) production via Sp1-dependent transcriptional inhibition.
Conclusions:
- SERCA2b is a critical molecular player in the development and maintenance of neuropathic pain.
- Targeting SERCA2b represents a promising therapeutic strategy for managing neuropathic pain.
- Alleviating ER stress through SERCA2b activation offers a novel pathway for pain treatment.
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