title: 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.
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.
authors.affiliation: Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Hans Jürgen
authors.initials: HJ
authors.lastname: Solinski
authors.forename: Franziska
authors.initials: F
authors.lastname: Petermann
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rothe
authors.forename: Ingrid
authors.initials: I
authors.lastname: Boekhoff
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Breit
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005727:Ganglia, Spinal / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D057809:HEK293 Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D054390:Receptors, CCR2 / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism; D050801:Ternary Complex Factors / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D051766:Early Growth Response Protein 1; D053496:Inositol 1,4,5-Trisphosphate Receptors; C488910:Itpr1 protein, rat; D050778:NFATC Transcription Factors; D010446:Peptide Fragments; D054390:Receptors, CCR2; D043562:Receptors, G-Protein-Coupled; D026362:Serum Response Factor; D050801:Ternary Complex Factors; C571042:bovine adrenal medulla 8-22; C510803:mas-related gene-X1 receptor, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019703:Calcineurin; D001920:Bradykinin; D002118:Calcium