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J. Biol. Chem., Vol. 275, Issue 39, 30701-30706, September 29, 2000

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A Primitive ATP Receptor from the Little Skate Raja erinacea^*

Jonathan A. Dranoff^§¶, Allison F. O'Neill^§, Ann Marie Franco, Shi-Ying Cai, Gregory C. Connolly^§, Nazzareno Ballatori^§, James L. Boyer^§, and Michael H. Nathanson^§

From the  Department of Medicine and Liver Study Unit, Yale University School of Medicine, New Haven, Connecticut 06520, the ^§ Mount Desert Island Biological Laboratories, Salisbury Cove, Maine 04672, and the  Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642

P2Y ATP receptors are widely expressed in mammalian tissues and regulate a broad range of activities. Multiple subtypes of P2Y receptors have been identified and are distinguished both on a molecular basis and by pharmacologic substrate preference. Functional evidence suggests that hepatocytes from the little skate Raja erinacea express a primitive P2Y ATP receptor lacking pharmacologic selectivity, so we cloned and characterized this receptor. Skate hepatocyte cDNA was amplified with degenerate oligonucleotide probes designed to identify known P2Y subtypes. A single polymerase chain reaction product was found and used to screen a skate liver cDNA library. A 2314-base pair cDNA clone was generated that contained a 1074-base pair open reading frame encoding a 357-amino acid gene product with 61-64% similarity to P2Y₁ receptors and 21-37% similarity to other P2Y receptor subtypes. Pharmacology of the putative P2Y receptor was examined using the Xenopus oocyte expression system and revealed activation by a range of nucleotides. The receptor was expressed widely in skate tissue and was expressed to a similar extent in other primitive organisms. Phylogenetic analysis suggested that this receptor is closely related to a common ancestor of the P2Y subtypes found in mammals, avians, and amphibians. Thus, the skate liver P2Y receptor functions as a primitive P2Y ATP receptor with broad pharmacologic selectivity and is related to the evolutionary forerunner of P2Y₁ receptors of higher organisms. This novel receptor should provide an effective comparative model for P2Y receptor pharmacology and may improve our understanding of nucleotide specificity among the family of P2Y ATP receptors.

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