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Vol. 59, Issue 1, 76-82, January 2001

A3 Adenosine Receptor Activation Triggers Phosphorylation of Protein Kinase B and Protects Rat Basophilic Leukemia 2H3 Mast Cells from Apoptosis

Zhenhai Gao,1 Bing-Sheng Li, Yuan-Ji Day, and Joel Linden

Departments of Cardiovascular Medicine (Z.G., J.L.) and Molecular Physiology and Biological Physics (Y.-J.D., J.L.), University of Virginia, Charlottesville, Virginia; and Laboratory of Neurochemistry, National Institute on Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (B.-S.L.)

Adenosine accumulates to high levels in inflamed or ischemic tissues and activates A3 adenosine receptors (ARs) on mast cells to trigger degranulation. Here we show that stimulation of rat basophilic leukemia (RBL)-2H3 mast-like cells with the A3 AR agonists N6-(3-iodo)benzyl-5'-N-methylcarboxamidodoadenosine (IB-MECA; 10 nM) or inosine (10 µM) stimulates phosphorylation of protein kinase B (Akt). IB-MECA (1 µM) also causes a >50% reduction in apoptosis caused by exposure of RBL-2H3 cells to UV light. Akt phosphorylation is not stimulated by 100 nM N6-cyclopentyladenosine (A1-selective) or CGS21680 (A2A-selective) and is absent in cells pretreated with wortmannin or pertussis toxin. The KI values of the AR antagonists BW-1433 and 8-sulfophenyltheophylline (8-SPT) were determined in radioligand binding assays for all four subtypes of rat ARs: BW-1433 (A1, 5.8 ± 1.0 nM; A2A, 240 ± 37; A2B, 30 ± 10; A3, 12,300 ± 3,700); 8-SPT (A1, 3.2 ± 1.2 µM; A2A, 57 ± 4; A2B, 2.2 ± 0.8; A3, >100). BW-1433 and the A3-slective antagonist MRS1523 (5 µM), but not 8-SPT (100 µM), block IB-MECA-induced protection from apoptosis, confirming the A3 AR as the mediator of the antiapoptotic response. The data suggest that adenosine and inosine activate Gi-coupled A3 ARs to protect mast cells from apoptosis by a pathway involving the beta gamma subunits of Gi, phosphatidylinositol 3-kinase beta , and Akt. We speculate that activation of A3 ARs on mast cells or other cells that express A3 ARs (e.g., eosinophils) may facilitate their survival and accumulation in inflamed tissues.

1 Current address: CV Therapeutics, Palo Alto, California.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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