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Volume 271, Number 46, Issue of November 15, 1996 pp. 29080-29087
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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A Guanine Nucleotide-independent Inwardly Rectifying Cation Permeability Is Associated with P2Y₁ Receptor Expression in Xenopus Oocytes

(Received for publication, July 24, 1996, and in revised form, August 27, 1996)

Scott M. O'Grady , Eric Elmquist , Theresa M. Filtz ^¶ , Robert A. Nicholas ^¶ and T. Kendall Harden ^¶

From the  Department of Physiology and Animal Sciences, University of Minnesota, St. Paul, Minnesota 55108 and the ^¶ Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599

The functional properties of the G protein-coupled P2Y₁ receptor were investigated in Xenopus oocytes. Incubation of oocytes expressing either the human or turkey P2Y₁ receptor with adenine nucleotide agonists resulted in an increase in Cl current and activation of a novel cation current with an inwardly rectifying current-voltage relationship. Activation of either the human P2Y₂ (P_2U-purinergic) or M1 muscarinic receptor expressed in oocytes resulted in an increase in Cl current similar to that observed in P2Y₁ receptor-expressing oocytes but had no effect on cation current. P2 receptor agonists stimulated both the cation current and Cl current in P2Y₁ receptor-expressing oocytes with EC₅₀ values and an order of potency (2-methylthioadenosine diphosphate > 2-methylthioadenosine triphosphate (2MeSATP) > ATP > UTP) that were similar to those previously observed for activation of phospholipase C in 1321N1 human astrocytoma cells stably expressing the human or turkey P2Y₁ receptor. The P2Y receptor antagonists suramin and pyridoxal phosphate 6-azophenyl-2-4-disulfonic acid both shifted to the right the concentration-response relationship for 2MeSATP for stimulation of oocyte currents. Although injection of oocytes with either GDPS (guanyl-5-yl thiophosphate) or GTPS (guanosine 5-3-O-(thio)triphosphate) resulted in loss of adenine nucleotide-promoted Cl channel activation, neither guanine nucleotide altered the 2MeSATP-stimulated cation current. These data are consistent with the view that activation of the novel cation current by the P2Y₁ receptor does not involve a G protein. Tail current analysis of the novel P2Y₁ receptor-associated cation conductance revealed that the open channel current-voltage relationship was outwardly rectifying with a reversal potential of 38 mV for the turkey P2Y₁ receptor and 36 mV for the human P2Y₁ receptor. Replacement of Na⁺ with K⁺ ions in the bathing solution produced a shift in reversal potential to near zero mV, but significant outward rectification remained. The cation current was not permeable to either Ca²⁺ or Ba²⁺ and exhibited steady-state inactivation at holding potentials below 60 mV. These results indicate that the P2Y₁ receptor exhibits both metabotropic properties and a novel G protein-independent ionotropic response when expressed in Xenopus oocytes.

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