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First published on June 2, 2004; DOI: 10.1124/mol.104.000224

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Received for publication March 10, 2004.
Revised May 26, 2004.
Accepted for publication May 28, 2004.

Identification of the P2Y12 receptor in nucleotide inhibition of exocytosis from bovine chromaffin cells

Steven Ennion 1, Andrew Powell 2, Elizabeth Seward 3*

1 University of Leicester 2 University of Birmingham 3 University of Sheffield

* Address correspondence to: E-mail: e.p.seward{at}sheffield.ac.uk

Abstract

Nucleotides are released from bovine chromaffin cells and take part in a feedback loop to inhibit further exocytosis. In order to identify the nucleotide receptors involved, we measured the effects of a range of exogenous nucleotides and related antagonists on voltage-operated calcium currents (ICa), intracellular calcium concentration ([Ca2+]i), and membrane capacitance changes ({Delta}Cm). In comparative parallel studies we also cloned the bovine P2Y12 receptor from chromaffin cells, and determined its properties by co-expression in Xenopus oocytes with inward- rectifier potassium channels made up of Kir3.1 and Kir3.4. In both systems, the agonist order of potency was essentially identical (2-MeSATP{approx}2-MeSADP>>ATP{approx}ADP>UDP). {alpha}{beta}Methylene-ATP and adenosine were inactive. UTP inhibited ICa in chromaffin cells (pEC50 4.89&plusmn0.11) but was essentially inactive at the cloned P2Y12 receptor. The relatively non-selective P2 antagonist pyridoxal-phosphate-6-azophenyl-2',4' disulfonic acid (PPADS) blocked nucleotide responses in both chromaffin cells and Xenopus oocytes, whilst the P2Y12 and P2Y13 selective antagonist, ARC69931MX blocked responses to ATP in both chromaffin cells and Xenopus oocytes but not to UTP in chromaffin cells. These results identify the P2Y12 receptor as a key component of the nucleotide inhibitory pathway, and also demonstrate the involvement of a UTP sensitive Gi/o coupled pyrimidine receptor.


Key words: Purinergic, Gi family, Calcium (G Protein Coupled Signals), Exocytosis


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