Abstract
Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bradykinin / pharmacology
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Calcineurin / metabolism
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Calcium / metabolism
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Cell Line
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Chemokine CCL2 / metabolism*
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Early Growth Response Protein 1 / genetics
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Early Growth Response Protein 1 / metabolism
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Enzyme Activation / drug effects
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Ganglia, Spinal / metabolism*
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Gene Expression Regulation / drug effects
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Genes, fos
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HEK293 Cells
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Humans
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Inositol 1,4,5-Trisphosphate Receptors / genetics
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Inositol 1,4,5-Trisphosphate Receptors / metabolism
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Mast Cells / metabolism*
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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NFATC Transcription Factors / metabolism
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Peptide Fragments / pharmacology
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Rats
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Receptors, CCR2 / genetics*
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Receptors, CCR2 / metabolism
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Sensory Receptor Cells / metabolism*
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Serum Response Factor / metabolism
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Ternary Complex Factors / metabolism
Substances
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Chemokine CCL2
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Early Growth Response Protein 1
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Inositol 1,4,5-Trisphosphate Receptors
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Itpr1 protein, rat
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NFATC Transcription Factors
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Peptide Fragments
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Receptors, CCR2
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Receptors, G-Protein-Coupled
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Serum Response Factor
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Ternary Complex Factors
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bovine adrenal medulla 8-22
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mas-related gene-X1 receptor, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Calcineurin
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Bradykinin
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Calcium
Grants and funding
This work was supported by a grant from the “Deutsche Forschungsgemeinschaft” [grant BR 3346/3–1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.