Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

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 v...

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Published in:PloS one 2013-03, Vol.8 (3), p.e58756
Main Authors: Solinski, Hans Jürgen, Petermann, Franziska, Rothe, Kathrin, Boekhoff, Ingrid, Gudermann, Thomas, Breit, Andreas
Format: Article
Language:English
Subjects:
Animals
Biology
Bradykinin - pharmacology
Calcineurin - metabolism
Calcium - metabolism
CC chemokine receptors
CCR2 protein
Cell culture
Cell Line
Chemokine CCL2 - secretion
Chemokines
Chronic pain
Connective tissues
Dorsal root ganglia
Early Growth Response Protein 1 - genetics
Early Growth Response Protein 1 - metabolism
Enzyme Activation - drug effects
G protein-coupled receptors
G proteins
Ganglia
Ganglia, Spinal - metabolism
Gene expression
Gene Expression Regulation - drug effects
Genes
Genes, fos
HEK293 Cells
Humans
Inflammation
Inositol 1,4,5-Trisphosphate Receptors - genetics
Inositol 1,4,5-Trisphosphate Receptors - metabolism
Kinases
Ligands
Lymphocytes
Lymphocytes T
Markers
Mast Cells - metabolism
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
Monocyte chemoattractant protein 1
Neuralgia
Neurons
Neuropathy
NF-AT protein
NFATC Transcription Factors - metabolism
Pain
Penicillin
Peptide Fragments - pharmacology
Phosphorylation
Phosphotransferases
Proteins
Rats
Receptors
Receptors, CCR2 - genetics
Receptors, CCR2 - metabolism
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Reporter gene
Sensory Receptor Cells - metabolism
Serum Response Factor - metabolism
Signaling
T cells
Ternary Complex Factors - metabolism
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0058756