Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the adenosine A(3) receptor (A3AR), which is a G(i/o) protein-coupled receptor, has attracted considerable interest as a potential target for drugs against asthma or inflammation, the in vivo evaluation of the antagonists using rodents in the first step of drug development has been hampered by the lack of highly potent antagonists for the rodent A3AR. To evaluate the pharmacological effects of human A3AR antagonists in mice, we previously generated A3AR-humanized mice, in which the mouse A3AR gene was replaced by its human counterpart. However, the human A3AR did not lead to the phosphoinositide 3-kinase (PI3K) gamma-signaling pathway such as IgE/antigen-dependent mast cell degranulation, probably due to the uncoupling of the mouse G(i/o) protein(s). To overcome the uncoupling, we here generated A3AR functionally humanized mice by replacing the mouse A3AR gene with a human/mouse chimeric A3AR sequence in which whole intracellular regions of the human A3AR were substituted for the corresponding regions of the mouse A3AR. The chimeric A3AR led to intracellular Ca(2+) elevation and activation of the PI3Kgamma-signaling pathway, which are equivalent to the actions induced by A3AR in wild-type mice. The human A3AR antagonist had the same binding affinities for the chimeric A3AR as the human A3AR and completely antagonized this potentiation. This is the first direct evidence that the uncoupling of mouse G protein(s) to the human A3AR is due to a sequence difference in the intracellular regions of A3AR. The A3AR functionally humanized mice can be widely employed for pharmacological evaluations of the human A3AR antagonists.
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PMID:Generation of adenosine A3 receptor functionally humanized mice for the evaluation of the human antagonists. 1630 Jul 45

Phosphatidylinositol 3-kinase (PI3K) has been recognized as an important downstream effector of high-affinity receptor for IgE (FcepsilonRI) signaling in mast cells, but little is known about the isoform specificity of PI3Ks on the FcepsilonRI-mediated migration toward the antigen (Ag). In the present study, we explored the role of PI3Kgamma on mast cell migration. The treatment of bone marrow-derived mast cells (BMMCs) with a PI3Kgamma inhibitor, AS605240, significantly repressed FcepsilonRI-induced degranulation and migration. The culture supernatants of wild-type mast cells stimulated with IgE and Ag attracted FcepsilonRIbeta(-/-) mast cells which did not express FcepsilonRI on their cell surface, indicating that the migration appears to be dependent on an autocrine/paracrine secretion of soluble factors from the mast cells. Adenosine, which is produced by mast cells, showed a strong activity to attract mast cells. Pertussis toxin (PTX) significantly inhibited the migration toward both the supernatant and adenosine. The supernatant from mast cells pretreated with wortmannin (Wort) and stimulated with IgE and Ag still exhibited the activity as chemoattractant, while the BMMCs pretreated with Wort did not migrate toward the supernatant. Although PTX significantly reduced the activation of AKT/PKB and migration, PTX had no effects on degranulation. These results suggest that PI3Kgamma activation through PTX-sensitive G-protein-coupled receptor as a secondary response of FcepsilonRI cross-linking regulates FcepsilonRI-mediated mast cell migration toward the Ag, while simultaneously activated PI3Kgamma through a PTX-insensitive pathway might have an effect on degranulation.
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PMID:PI3Kgamma differentially regulates FcepsilonRI-mediated degranulation and migration of mast cells by and toward antigen. 1949 8