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Vol. 61, Issue 2, 415-424, February 2002
Department of Clinical and Experimental Medicine, Pharmacology
Unit, University of Ferrara, Italy and "Centro Nazionale di
Eccellenza per lo Sviluppo di Metodologie Innovative per lo Studio ed
il Trattamento delle Patologie Infiammatorie" Ferrara, Italy
(S.G., K.V., S.M., E.C., V.I., P.A.B.); King Pharmaceuticals, Cary,
North Carolina (E.L.); Department of Pharmaceutical Sciences,
University of Ferrara, Ferrara, Italy (P.G.B.)
This work compares the pharmacological and biochemical properties of
A3 adenosine receptors in human polymorphonuclear
neutrophil granulocytes (PMNs) and promyelocytic HL60 cells. The gene
expression of A3 receptors was examined by reverse
transcription-polymerase chain reaction experiments, whereas the amount
of A3 subtype on the plasma membrane was quantified
by using the high-affinity and selective A3 antagonist
[3H]5N-(4-methoxyphenyl-carbamoyl)amino-8-propyl-2-(2-furyl)pyrazolo-[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine ([3H]MRE 3008F20). Saturation experiments reveal a
single high-affinity binding site with KD
values of 2.3 ± 0.3, 2.6 ± 0.4 nM, and
Bmax values of 430 ± 35, 345 ± 31 fmol/mg of protein for PMNs and HL60 cells, respectively.
Competition of radioligand binding by adenosine ligands displays a rank
order of potency typical of the A3 subtype. EC50 values of
N6-(3-iodo-benzyl)-2-chloro-adenosine-5'-N-methyluronamide
(Cl-IB-MECA) for inhibition of cAMP levels via A3 receptors
are in good agreement with the binding data; furthermore, the response
is potently inhibited by MRE 3008F20. In contrast, the high micromolar
concentrations of Cl-IB-MECA and MRE 3008F20 in stimulating and
blocking Ca2+ mobilization, respectively, are not
completely consistent with the involvement of an A3
receptor. Furthermore, an important finding of this work is that the
inhibition of PMNs oxidative burst is predominantly
A2A-mediated, even though an effect of A3
subtype could not be excluded. This conclusion is based on potent
blockade of Cl-IB-MECA-mediated inhibition of oxidative burst by SCH
58261 and a minor but significant blockade by MRE 3008F20. In
conclusion, HL60 cells express A3 receptors similar
to those in PMNs, thus providing a useful model for investigation of
biochemical pathways leading to A3 receptor activation.
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