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Vol. 57, Issue 5, 926-931, May 2000
Department of Physiology and Pharmacology, University of
Strathclyde, Glasgow, Great Britain (C.K.); and Department of
Pharmacology, University of North Carolina, School of Medicine, Chapel
Hill, North Carolina (A.-D.Q., C.L.H., T.K.H., K.H., R.A.N.)
The nucleotide selectivities of the human P2Y4
(hP2Y4) and rat P2Y4 (rP2Y4)
receptor stably expressed in 1321N1 human astrocytoma cells were
determined by measuring increases in intracellular [Ca2+]
under conditions that minimized metabolism, bioconversion, and endogenous nucleotide release. In cells expressing the
hP2Y4 receptor, UTP, GTP, and ITP all increased
intracellular [Ca2+] with a rank order of potency of UTP
(0.55) > GTP (6.59) = ITP (7.38), (EC50, µM).
ATP, CTP, xanthine 5'-triphosphate (XTP), and diadenosine
5',5
-P1,P4-tetraphosphate
(Ap4A), all at 100 µM, were inactive at the
hP2Y4 receptor. In cells expressing the rP2Y4
receptor, all seven nucleotides increased intracellular
[Ca2+] with similar maximal effects and a rank order of
potency of UTP (0.20) > ATP (0.51) > Ap4A
(1.24) 
ITP (1.82) GTP (2.28) > CTP (7.24) > XTP
(22.9). Because ATP is inactive at the hP2Y4 receptor, we
assessed whether ATP displayed antagonist activity. When coapplied, ATP
shifted the concentration-response curve to UTP rightward in a
concentration-dependent manner, with no change in the maximal response.
A Schild plot derived from these data gave a pA2 value of
6.15 (KB = 708 nM) and a slope near
unity. Additionally, CTP and Ap4A (each at 100 µM)
inhibited the response to an EC50 concentration of UTP by
~40 and ~50%, respectively, whereas XTP had no effect. The
inhibitory effects of ATP, CTP, and Ap4A were reversible on
washout. Thus, ATP is a potent agonist at the rP2Y4
receptor but is a competitive antagonist with moderate potency at the
hP2Y4 receptor.
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