Orai1 is a crucial downstream partner of group i metabotropic glutamate receptor signaling in dorsal horn neurons

Jingsheng Xia, Yannong Dou, Yixiao Mei, Frances M. Munoz, Ruby Gao, Xinghua Gao, Daling Li, Patrick Osei-Owusu, James Schiffenhaus, Alex Bekker, Yuan Xiang Tao, Huijuan Hu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Group I metabotropic glutamate receptors (group I mGluRs) have been implicated in several central nervous system diseases including chronic pain. It is known that activation of group I mGluRs results in the production of inositol triphosphate (IP3) and diacylglycerol that leads to activation of extracellular signal-regulated kinases (ERKs) and an increase in neuronal excitability, but how group I mGluRs mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that group I mGluRs recruit Orai1 as part of its downstream signaling pathway in dorsal horn neurons. We demonstrate that neurotransmitter glutamate induces STIM1 puncta formation, which is not mediated by N-Methyl-D-aspartate (NMDA) or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Glutamate-induced Ca2+entry in the presence of NMDA or AMPA receptor antagonists is eliminated in Orai1-deficient neurons. Dihydroxyphenylglycine (DHPG) (an agonist of group I mGluRs)-induced Ca2+entry is abolished by Orai1 deficiency, but not affected by knocking down of transient receptor potential cation channel 1 (TRPC1) or TRPC3. Dihydroxyphenylglycine-induced activation of ERKs and modulation of neuronal excitability are abolished in cultured Orai1-deficient neurons. Moreover, DHPG-induced nociceptive behavior is markedly reduced in Orai1-deficient mice. Our findings reveal previously unknown functional coupling between Orai1 and group I mGluRs and shed light on the mechanism underlying group I mGluRs-mediated neuronal plasticity.

Original languageEnglish (US)
Pages (from-to)652-664
Number of pages13
JournalPain
Volume163
Issue number4
DOIs
StatePublished - Apr 1 2022

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Keywords

  • ERK
  • Metabotropic glutamate receptors
  • Orai1
  • Pain
  • Spinal cord dorsal horn
  • Store-operated calcium channels

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