Journal article
PGE2 Potentiates Orai1-Mediated Calcium Entry Contributing to Peripheral Sensitization
The Journal of neuroscience, v 44(1), 0329232023
03 Jan 2024
PMID: 37952941
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Peripheral sensitization is one of the primary mechanisms underlying the pathogenesis of chronic pain. However, candidate molecules involved in peripheral sensitization remain incompletely understood. We have shown that store-operated calcium channels (SOCs) are expressed in the dorsal root ganglion (DRG) neurons. Whether SOCs contribute to peripheral sensitization associated with chronic inflammatory pain is elusive. Here we report that global or conditional deletion of Orai1 attenuates Complete Freund's adjuvant (CFA)-induced pain hypersensitivity in both male and female mice. To further establish the role of Orai1 in inflammatory pain, we performed calcium imaging and patch-clamp recordings in wild-type (WT) and Orai1 knockout (KO) DRG neurons. We found that SOC function was significantly enhanced in WT but not in Orai1 KO DRG neurons from CFA- and carrageenan-injected mice. Interestingly, the Orai1 protein level in L3/4 DRGs was not altered under inflammatory conditions. To understand how Orai1 is modulated under inflammatory pain conditions, prostaglandin E2 (PGE2) was used to sensitize DRG neurons. PGE2-induced increase in neuronal excitability and pain hypersensitivity was significantly reduced in Orai1 KO mice. PGE2-induced potentiation of SOC entry (SOCE) was observed in WT, but not in Orai1 KO DRG neurons. This effect was attenuated by a PGE2 receptor 1 (EP1) antagonist and mimicked by an EP1 agonist. Inhibition of Gq/11, PKC, or ERK abolished PGE2-induced SOCE increase, indicating PGE2-induced SOCE enhancement is mediated by EP1-mediated downstream cascade. These findings demonstrate that Orai1 plays an important role in peripheral sensitization. Our study also provides new insight into molecular mechanisms underlying PGE2-induced modulation of inflammatory pain.
Store-operated calcium channel (SOC) Orai1 is expressed and functional in dorsal root ganglion (DRG) neurons. Whether Orai1 contributes to peripheral sensitization is unclear. The present study demonstrates that Orai1-mediated SOC function is enhanced in DRG neurons under inflammatory conditions. Global and conditional deletion of Orai1 attenuates complete Freund's adjuvant (CFA)-induced pain hypersensitivity. We also demonstrate that prostaglandin E2 (PGE2) potentiates SOC function in DRG neurons through EP1-mediated signaling pathway. Importantly, we have found that Orai1 deficiency diminishes PGE2-induced SOC function increase and reduces PGE2-induced increase in neuronal excitability and pain hypersensitivity. These findings suggest that Orai1 plays an important role in peripheral sensitization associated with inflammatory pain. Our study reveals a novel mechanism underlying PGE2/EP1-induced peripheral sensitization. Orai1 may serve as a potential target for pathological pain.
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Details
- Title
- PGE2 Potentiates Orai1-Mediated Calcium Entry Contributing to Peripheral Sensitization
- Creators
- Dongyu Wei - Drexel UniversityHareram Birla - Rutgers, The State University of New JerseyYannong Dou - Drexel UniversityYixiao Mei - Drexel UniversityXiaodong Huo - Rutgers, The State University of New JerseyVictoria Whitehead - Rutgers, The State University of New JerseyPatrick Osei-Owusu - Rutgers, The State University of New JerseyStefan Feske - New York UniversityGiovanna Patafio - Rutgers, The State University of New JerseyYuanxiang Tao - Rutgers New Jersey Medical SchoolHuijuan Hu - Drexel University
- Publication Details
- The Journal of neuroscience, v 44(1), 0329232023
- Publisher
- Society for Neuroscience
- Grant note
- R01 NS128403 / NINDS NIH HHS R01 NS117484 / NINDS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001294745300010
- Scopus ID
- 2-s2.0-85181761123
- Other Identifier
- 991022202084904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences