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Vol. 59, Issue 1, 76-82, January 2001
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 
subunits of Gi, phosphatidylinositol 3-kinase , 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.
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