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Molecular Pharmacology, Volume 52, Issue 5, 846-860
Departments of Medicine (Cardiology), and Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908 (J.A.A., X.J., T.C.W., J.L.), and Department of Medicine, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California 94143 (G.H.C.)
We cloned and characterized the canine A3 adenosine
receptor (AR) and examined AR-induced degranulation of the BR line of canine mastocytoma cells. Canine A3AR transcript is found
predominantly in spleen, lung, liver, and testes and encodes a
314-amino acid heptahelical receptor.
125I-N6-Aminobenzyladenosine
binds to two affinity states of canine A3AR with
KD values of 0.7 ± 0.1 and
16 ± 0.8 nM, reflecting G protein-coupled and
-uncoupled receptors, respectively. Xanthine antagonists bind with
similar affinities to human, canine, and rabbit receptors but with
80-400-fold lower affinities to rat A3AR. Although canine
BR mastocytoma cells contain A1AR, A2BAR, and
A3AR, degranulation seems to be mediated primarily by
A2BARs stimulated by the nonselective agonist
5
-N-ethylcarboxamidoadenosine (NECA) but not by the
A3-selective agonist
N6-(3-iodobenzyl)adenosine-5-N-methylcarboxamide.
NECA-stimulated degranulation is not prevented by pertussis toxin and
is blocked by enprofylline (Ki = 7 µM), an antiasthmatic xanthine with low affinity
(Ki > 100 µM)
for A1AR, A2AAR, and A3AR. NECA
increases canine mastocytoma cell cAMP, Ca2+, and inositol
trisphosphate levels; these responses are antagonized half-maximally by
7-15 µM enprofylline. The results suggest that (i)
the cloned canine A3AR is structurally and
pharmacologically more similar to human than to rat A3AR;
(ii) the A2BAR, and not the A1AR or
A3AR, is principally responsible for adenosine-mediated degranulation of canine BR mastocytoma cells; and (iii) the BR cell
A2BAR couples to both Ca2+ mobilization and
cAMP accumulation. Although A2B receptors play a major role
in the regulation of BR mast cell degranulation, multiple AR subtypes
and G proteins may influence mast cell functions.
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