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Vol. 56, Issue 4, 705-713, October 1999
Departments of Internal Medicine (J.L., T.T., H.F., A.S.R.),
Molecular Physiology and Biological Physics (J.L.), and Biochemistry
(X.J.), University of Virginia, Charlottesville, Virginia
Recombinant human A2B adenosine receptors
(A2BARs) and receptors extended on the amino terminus with
hexahistidine and the FLAG epitope, DYKDDDDK
(H/F-A2B) were stably overexpressed (to >20,000
fmol/mg protein) in human embryonic kidney 293 cells
(HEK-A2B). By Western blotting, the H/F-A2B
receptor runs as a 34.8-kDa glycoprotein. Pharmacological
properties of A2BARs were characterized with
125I-3-aminobenzyl-8-phenyl-(4-oxyacetic
acid)-1-propylxanthine (KD, 36 nM). In
competition binding assays, the affinity of agonists is reduced by
substitution on either the N6- or the C-2
position of the adenine ring, whereas 5'-substitutions increase
affinity, resulting in the potency order:
5'-N-ethylcarboxamidoadenosine (NECA) 
N6-aminobenzyl-NECA
2-chloroadenosine > 2-[4-(2-carboxyethyl)phenethylamino]-NECA (CGS21680) > N6-aminobenzyladenosine. The
A2BAR is potently blocked by the
A2A-selective antagonist
4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo-[2,3-a][1,3,5] triazin-5-yl-amino]ethyl)phenol
(ZM241385; KI, 32 nM for A2B, 1.4 nM for A2A) and the A1 selective antagonist
8-cyclopentyl-1,3-dipropylxanthine (KI, 50.5 nM for A2B; 2.5 nM for A1). The
KI values for the antiasthmatic xanthines,
theophylline (7.8 µM) and enprofylline (6.4 µM), are below their
therapeutic plasma concentrations (20 to 50 µM), and agree with
KI determinations for inhibition of
NECA-stimulated cAMP accumulation in HEK-A2B cells. NECA or
N6-(2-iodo)benzyl-5'-N-methylcarboxamidodoadenosine
(IB-MECA) stimulate inositol trisphosphates and calcium accumulation in
HEK-A2B or HEK-A3 cells, respectively, but only
the A3 response is prevented by pertussis toxin. In human
HMC-1 mast cells, A2BAR activation stimulates calcium
mobilization and cAMP accumulation. We conclude that
HEK-A2B cells and HMC-1 mast cells possess
A2BAR glycoproteins that are coupled to both
Gq/11 and Gs.
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