Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

Abstract

Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-β2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders.

Influence of GRPR and BDNF/TrkB signaling on the viability of breast and gynecologic cancer cells

“…Notably, in experiments examining cancer cell growth (27,30,31), as well as in other experimental models (32)(33)(34), GRPR agonists and antagonists often show drug-response patterns, in which intermediate doses have more pronounced biological, whereas higher doses have no or even contrary effects. Moreover, the lack of a significant effect of RC-3095 in the present study might be owed to its lower potency compared to RC-3940-II.…”

Changes in FABP1 and gastrin receptor expression in the testes of rats that have undergone electrical injury

“…The expression of GRPR is elevated in mucosa adjacent to head and neck squamous cell carcinoma (HNSCC) compared with mucosa from cancer-free controls, suggesting that elevated GRPR expression may indicate presence of HNSCC (35). GRP acts as a neuropeptide through G protein-coupled receptors involved in signal transmission in the central and peripheral nervous systems (36). It has also been proposed that GRPR is an alternative chemotactic receptor that may be involved in the pathogenesis of inflammatory disorders (36).…”

“…GRP acts as a neuropeptide through G protein-coupled receptors involved in signal transmission in the central and peripheral nervous systems (36). It has also been proposed that GRPR is an alternative chemotactic receptor that may be involved in the pathogenesis of inflammatory disorders (36). In addition, gastrin plays an important role in the male reproductive system (37,38).…”

Anti-inflammatory Effects of a Small Molecule Gastrin-Releasing Peptide Receptor Antagonist on Adjuvant-Induced Rheumatoid Arthritis in Rats

“…17 10 and 20 nM of RH-1402 significantly inhibited the effect of GRP on neutrophil migration with a dose dependent relationship ( Figure 4). In mice, 3, 6 and 9 μg of RH-1402 also inhibited neutrophil migration ( Figure 5).…”

“…Heparin treated peripheral venous blood of healthy human volunteers was used to isolate human neutrophils. The inhibiting effect was evaluated using a previously described method, 17 briefly, the used transwell system contains a top well and a bottom, and they are partitioned off with a 5 μm polycarbonate membrane. 1 nM GRP was added to the bottom wells as chemotaxis in RPMI 1640 medium with 2% FCS.…”