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Xia J, Dou Y, Mei Y, et al. Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons. Pain. 2021;doi: 10.1097/j.pain.0000000000002396.
Xia, J., Dou, Y., Mei, Y., Munoz, F. M., Gao, R., Gao, X., Li, D., Osei-Owusu, P., Schiffenhaus, J., Bekker, A., Tao, Y. X., & Hu, H. (2021). Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons. Pain, . https://doi.org/10.1097/j.pain.0000000000002396
Xia, Jingsheng, et al. "Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons." Pain vol. (2021). doi: https://doi.org/10.1097/j.pain.0000000000002396
Xia J, Dou Y, Mei Y, Munoz FM, Gao R, Gao X, Li D, Osei-Owusu P, Schiffenhaus J, Bekker A, Tao YX, Hu H. Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons. Pain. 2021 Jul 08; doi: 10.1097/j.pain.0000000000002396. Epub 2021 Jul 08. PMID: 34252911.
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Pain. 2021 Jul 08; doi: 10.1097/j.pain.0000000000002396. Epub 2021 Jul 08.

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

Pain

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

Affiliations

  1. Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ 07103 Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102.

PMID: 34252911 DOI: 10.1097/j.pain.0000000000002396

Abstract

ABSTRACT: Group I metabotropic glutamate receptors (mGluR1 and mGluR5, mGluR1/5) have been implicated in several CNS diseases including chronic pain. It is known that activation of mGluR1/5 results in production of inositol triphosphate (IP3) and diacylglycerol (DAG) that leads to activation of extracellular signal-regulated kinases (ERK1/2) and an increase in neuronal excitability, but how mGluR1/5 mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry (SOCE) and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that mGluR1/5 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 NMDA or AMPA receptors. Glutamate-induced Ca2+ entry in the presence of NMDA/AMPA receptor antagonists is eliminated in Orai1-deficient neurons. DHPG (an agonist of mGluR1/5)-induced Ca2+ entry is abolished by Orai1 deficiency, but not affected by knocking down of TRPC1 or TRPC3. DHPG-induced activation of ERK1/2 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 mGluR1/5 and shed light on the mechanism underlying mGluR1/5-mediated neuronal plasticity.

Copyright © 2021 International Association for the Study of Pain.

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