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Journal article
Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons
Pain (Amsterdam), v 163(4), pp 652-664
01 Apr 2022
PMID: 34252911
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 kineses (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 signing 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 alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic add (AMPA) receptors. Glutamate-induced Ca2+ entry in the presence of NMDA or AMPA receptor antagonists is eiminated in Orai1-deficient neurons. Dhydroxyphenylglycine (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 excitabity 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 couping between Orai1 and group I mGluRs and shed light on the mechanism underlying group I mGluRs-mediated neuronal plasticity.
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- Title
- Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons
- Creators
- Jingsheng Xia - Drexel UniversityYannong Dou - Drexel Univ, Dept Pharmacol & Physiol, Coll Med, Philadelphia, PA 19104 USAYixiao Mei - Rutgers New Jersey Med Sch, Dept Anesthesiol, 185 S Orange Ave, Newark, NJ 07103 USAFrances M. Munoz - Drexel Univ, Dept Pharmacol & Physiol, Coll Med, Philadelphia, PA 19104 USARuby Gao - Drexel Univ, Dept Pharmacol & Physiol, Coll Med, Philadelphia, PA 19104 USAXinghua Gao - Drexel Univ, Dept Pharmacol & Physiol, Coll Med, Philadelphia, PA 19104 USADaling Li - Rutgers New Jersey Med Sch, Dept Anesthesiol, 185 S Orange Ave, Newark, NJ 07103 USAPatrick Osei-Owusu - Drexel UniversityJames Schiffenhaus - Rutgers New Jersey Med Sch, Dept Anesthesiol, 185 S Orange Ave, Newark, NJ 07103 USAAlex Bekker - Rutgers New Jersey Med Sch, Dept Anesthesiol, 185 S Orange Ave, Newark, NJ 07103 USAYuan-Xiang Tao - Rutgers New Jersey Med Sch, Dept Anesthesiol, 185 S Orange Ave, Newark, NJ 07103 USAHuijuan Hu - Drexel Univ, Dept Pharmacol & Physiol, Coll Med, Philadelphia, PA 19104 USA
- Publication Details
- Pain (Amsterdam), v 163(4), pp 652-664
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 13
- Grant note
- R01NS087033 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000770384200024
- Scopus ID
- 2-s2.0-85127729776
- Other Identifier
- 991019169109204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Anesthesiology
- Clinical Neurology
- Neurosciences