PGE2 Potentiates Orai1-Mediated Calcium Entry Contributing to Peripheral Sensitization.

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.Significance Statement 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.

Ecological regime shifts reduced burial ability of aromatic hydrocarbons by both inland and coastal waters but driven by various nutrients.

Huge synthetic chemicals and hydrocarbons have been released to inland waters and oceans, composing anthropogenic dissolved organic carbon (ADOC). They complement a large budget for CO2. Burial by inland and coastal marine sediments is crucial to reduce this budget. How ecological regime shifts influence the burial ability of ADOC by inland waters and coastal oceans, and what are the differences between them remain largely unknown. We collected sediment cores from an inland lake (Lake Qianhu) and the largest coastal lagoon (Lagoon Pinqing) in China, and chose 16 polycyclic aromatic hydrocarbons (PAHs) to address these issues. Burial ability of PAHs by sediments decreased by 55.1% - 98.5% in Lagoon Pinqing in the period from 1963 to 2018, and by 91.5% - 99.5% in Lake Qianhu in the period from 1970 to 2018. Burial ability and its decrease rate for most PAHs in Lagoon Pinqing were larger than those in Lake Qianhu in the same period. PAHs with higher hydrophobicity were more ready to be buried by both lake sediments and lagoon sediments. Burial ability of most PAHs in Lagoon Pinqing was negative correlated with total phosphorus concentration. In contrast, burial ability of most PAHs in Lake Qianhu was negative correlated with total nitrogen concentration. Regime shifted from phytoplankton to submerged macrophytes dominance in the year of 1976, and from submerged macrophytes to phytoplankton dominance in the year of 1999 in Lagoon Pinqing, driven by nitrogen. Regime shifted from vascular plants to phytoplankton dominance in Lake Qianhu in the year of 1991, driven by phosphorus. Different aromaticity and sources of organic matter related to regime shifts were responsible for the discrepancy of burial ability for PAHs by sediments of these two waters. Our study suggests that burial ability of ADOC by inland and coastal marine sediments will be reduced if eutrophication results in ecological regime shifts, which may undermine the efforts to mitigate global warming.