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Regulation of neuropathic pain by microglial Orai1 channels

Microglia are important mediators of neuroinflammation, which underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. Here, we investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca2+ signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglial proliferation in the dorsal horn, spinal cytokine levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in microglial Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Unexpectedly, these protective effects were not seen in female mice, revealing sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. Together, these findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.

 

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The statement describes a study investigating the role of Orai1 channels in microglia-mediated neuroinflammation following nerve injury and its contribution to neuropathic pain. The researchers found that deleting Orai1 in microglia attenuated Ca2+ signaling and the production of inflammatory cytokines by proalgesic agonists, resulting in mitigation of pain hyperalgesia in microglial Orai1 knockout mice. Additionally, a small-molecule Orai1 inhibitor similarly mitigated allodynia in male mice. However, the protective effects were not observed in female mice, indicating sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. The study sheds light on a potential molecular checkpoint controlling microglial reactivity and its role in neuropathic pain, with implications for developing sex-specific therapeutic strategies.

Related Products

Cat.No. Product Name Information
S6834 Zegocractin (CM 4620) Zegocractin (CM 4620) is an inhibitor of calcium-release activated calcium-channel (CRAC channel). CM4620 inhibits Orai1/STIM1-mediated Ca2+ currents and Orai2/STIM1-mediated currents with IC50 of near 120 nM and 900 nM, respectively.

Related Targets

Calcium Channel