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Vol. 54, Issue 6, 1118-1123, December 1998
Department of Pharmacology, University of North Carolina School of
Medicine, Chapel Hill, North Carolina 27599-7365
The agonist selectivity for adenosine di- and triphosphates was
determined for the human P2Y1 receptor stably expressed in human 1321N1 astrocytoma cells and was studied under conditions in
which nucleotide metabolism was both minimized and assessed. Cells were
grown at low density on glass coverslips, encased in a flow-through
chamber, and continuously superfused with medium, and Ca2+
responses to nucleotides were quantified. Superfusion with high performance liquid chromatographically purified ADP, ATP,
2-methylthio-ADP, and 2-methylthio-ATP resulted in rapid
Ca2+ responses, with EC50 values of 10 ± 5, 304 ± 51, 2 ± 1, and 116 ± 50 nM,
respectively. Similar peak responses were observed with maximal
concentrations of these four agonists and with the hydrolysis-resistant adenine nucleoside triphosphate
adenosine-5'-O-(3-thiotriphosphate). No conversion of
[3H]ATP to [3H]ADP occurred under these
conditions. Similar full agonist activities of ATP, 2-methylthio-ATP,
and ADP were observed in human embryonic kidney 293 cells, which
natively express the P2Y1 receptor. In contrast to these
results, Leon et al. [FEBS Lett
403:26-30 (1997)] and Hechler et al.
[Mol Pharmacol 53:727-733 (1998)] recently
reported that, whereas ADP and 2-methylthio-ADP were agonists, ATP and
2-methylthio-ATP were weak antagonists in studies of the human
P2Y1 receptor expressed in human Jurkat cells. To assess
whether differences in the degree of receptor reserve might explain
this discrepancy of results, P2Y1 receptor-expressing 1321N1 cells were incubated for 24 hr with
adenosine-5'-O-(2-thiodiphosphate), with the goal of
down-regulating the level of functional receptors. Pretreatment with
adenosine-5'-O-(2-thiodiphosphate) resulted in a 10-fold
rightward shift in the concentration-effect curve for ADP; in contrast,
the agonist activity of ATP was completely abolished. Taken together,
our results indicate that adenosine di- and triphosphates are agonists
at the human P2Y1 receptor. However, the intrinsic efficacy
of ATP is less than that of ADP, and the capacity of ATP to activate
second messenger responses through this receptor apparently depends on
the degree of P2Y1 receptor reserve.
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