Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigated the role of PGE(2) in mouse mastocytoma P-815 cell adhesion to extracellular matrix proteins (ECMs) in vitro. We report that PGE(2) accelerated ProNectin F(TM) (a proteolytic fragment of fibronectin)-mediated adhesion, which was abolished by addition of the GRGDS peptide, an inhibitor of the RDG binding site of ProNectin F(TM). We show that the cAMP level and cAMP-regulated protein kinase (PKA) activity are critical mediators of this PGE(2) effect, because the cell-permeable cAMP analogue 8-Br-cAMP accelerated P-815 cell adhesion to ProNectin F(TM) and the pharmacological inhibitor of PKA, H-89, blocked PGE(2)-mediated adhesion. Consistent with mRNA expression of the G(s)-coupled EP4- and G(i)-coupled EP3-PGE receptor subtypes, P-815 cell adhesion was accelerated by treatment with a selective EP4 agonist, ONO-AE1-329, but not a selective EP1/EP3 agonist, sulprostone. However, simultaneous treatment with ONO-AE1-329 and sulprostone resulted in augmentation of both the cAMP level and cell adhesion. The augmentation of EP3-mediated cAMP synthesis was dose-dependent, without affecting the half-maximal concentration for EP4-mediated G(s)-activity, which was inhibited by a G(i) inhibitor, pertussis toxin. In conclusion, these findings suggest that PGE(2) accelerates RGD-dependent adhesion via cooperative activation between EP3 and EP4 and contributes to the recruitment of mast cells to the ECM during inflammation.
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PMID:Induction of adherent activity in mastocytoma P-815 cells by the cooperation of two prostaglandin E2 receptor subtypes, EP3 and EP4. 1263 75

Four prostaglandin E (EP) receptor subtypes have been identified and cloned, designated as EP1, EP2, EP3 and EP4. These EP receptors are members of the G-protein coupled receptor family. EP3 receptor signals are primarily involved in inhibition of adenylyl cyclase via Gi activation, while EP2 and EP4 receptor signals cause a stimulation of adenylyl cyclase via Gs activation. Immune cells, such as mast cells, express multiple EP subtypes on their cell membranes, but few studies have been conducted to understand exactly what signals the main flow for the multiple subtypes expressing immune cells. We previously demonstrated that activation of Gi-coupled EP3 receptor exhibited a cooperative effect on cAMP synthesis induced by Gs-coupled EP2 receptor in COS-7 cells. Here we report that a selective EP4 agonist-induced adenylyl cyclase activity was augmented by simultaneous addition of a selective EP3 agonist in mastocytoma P-815 cells, which express mRNAs for both EP3 and EP4 subtypes. The augmentation in cAMP synthesis was found to be pertussis toxin-sensitive. P-815 cells are demonstrated to bind to Pronectin-F, a proteolytic fragment of fibronectin, in adhesion protein of the extracellular matrix, by addition of PGE2, which is mediated by PKA. The binding of P-815 cells to Pronectin-F mediated by EP4 receptor was augmented by the EP3 receptor. These findings indicate that two subtypes of PGE2 receptors, EP3 and EP4, cooperatively activate the cAMP-mediated adhesion event through induction of fibronectin ligand elicited by PGE2 in P-815 cells. Furthermore, the PGE2-induced adhesion response may contribute to the mast cell recruitment function on extracellular matrix during inflammation.
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PMID:[Cooperation of two subtypes of PGE2 receptor, Gi coupled EP3 and Gs coupled EP2 or EP4 subtype]. 1457 29

Accumulating evidence has indicated that mast cells can modulate a wide variety of immune responses. Migration and adhesion play a critical role in regulation of tissue mast cell function, in particular, under inflammatory conditions. We previously demonstrated that prostaglandin (PG) E(2) stimulates adhesion of a mouse mastocytoma cell line, P-815, to the Arg-Gly-Asp (RGD)-enriched matrix through cooperation between two PGE(2) receptor subtypes: EP3 and EP4 (Hatae N, Kita A, Tanaka S, Sugimoto Y, Ichikawa A. J Biol Chem 278: 17977-17981, 2003). We here investigated PGE(2)-induced adhesion of IL-3-dependent bone marrow-derived cultured mast cells (BMMCs). In contrast to the elevated cAMP-dependent adhesion of P-815 cells, EP3-mediated Ca(2+) mobilization plays a pivotal role in PGE(2)-induced adhesion of BMMCs. Adhesion and Ca(2+) mobilization induced by PGE(2) were abolished in the Ptger3(-/-) BMMCs and were significantly suppressed by treatment with pertussis toxin, a phospholipase C inhibitor, U-73122, and a store-operated Ca(2+) channel inhibitor, SKF 36965, indicating the involvement of G(i)-mediated Ca(2+) influx. We then investigated PGE(2)-induced adhesion of peritoneal mast cells to the RGD-enriched matrix. EP3 subtype was found to be the dominant PGE receptor that expresses in mouse peritoneal mast cells. PGE(2) induced adhesion of the peritoneal mast cells of the Ptger3(+/+) mice, but not that of the Ptger3(-/-) mice. In rat peritoneal mast cells, PGE(2) or an EP3 agonist stimulated both Ca(2+) mobilization and adhesion to the RGD-enriched matrix. These results suggested that the EP3 subtype plays a pivotal role in PGE(2)-induced adhesion of murine mast cells to the RGD-enriched matrix through Ca(2+) mobilization.
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PMID:Essential role of EP3 subtype in prostaglandin E2-induced adhesion of mouse cultured and peritoneal mast cells to the Arg-Gly-Asp-enriched matrix. 1881 28


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