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Characterization of a Ca²⁺ Response to Both UTP and ATP at Human P2Y₁₁ Receptors: Evidence for Agonist-Specific Signaling

Cell Signalling Laboratory, School of Pharmacy, De Montfort University, Leicester, United Kingdom

Previous reports on heterologously-expressed human P2Y₁₁ receptors have indicated that ATP, but not UTP, is an agonist stimulating both phosphoinositidase C and adenylyl cyclase. Consistent with these findings, we report that in 1321N1 cells expressing human P2Y₁₁ receptors, UTP stimulation did not lead to accumulation of inositol(poly)phosphates under conditions in which ATP gave a robust, concentration-dependent effect. Unexpectedly, however, both UTP and ATP stimulated increases in cytosolic Ca²⁺ concentration ([Ca²⁺]_c), with both nucleotides achieving similar EC₅₀ and maximal responses. The responses to maximally effective concentrations of ATP and UTP were not additive. The [Ca²⁺]_c increase in response to UTP was less dependent on extracellular Ca²⁺ than was the response to ATP. AR-C67085 (2-propylthio-,-difluoromethylene-D-ATP, a P2Y₁₁-selective agonist), adenosine 5'-O-(3-thiotriphosphate), and benzoyl ATP were all full agonists with potencies similar to those of ATP and UTP. In desensitization experiments, exposure to ATP resulted in loss of the UTP response; this response was more sensitive to desensitization than that of ATP. Pertussis toxin pretreatment attenuated the response to UTP but left the ATP response unaffected. The presence of 2-aminoethyl diphenylborate differentially affected the responses of ATP and UTP. No mRNA transcripts for P2Y₂ or P2Y₄ were detectable in the P2Y₁₁-expressing cells. We conclude that UTP is a Ca²⁺-mobilizing agonist at P2Y₁₁ receptors and that ATP and UTP acting at the same receptor recruit distinct signaling pathways. This example of agonist-specific signaling is discussed in terms of agonist trafficking and differential signal strength.

Address correspondence to: Prof. Mike Boarder, Cell Signaling Laboratory, School of Pharmacy, De Montfort University, The Hawthorn Building, Leicester LE1 9BH, England. E-mail mboarder{at}dmu.ac.uk

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