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Am J Physiol Cell Physiol 286: C264-C271, 2004. First published November 12, 2003; doi:10.1152/ajpcell.00287.2003
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RECEPTORS AND SIGNAL TRANSDUCTION

Molecular mechanism of nucleotide-induced primary granule release in human neutrophils: role for the P2Y2 receptor

John Meshki, Florin Tuluc, Ovidiu Bredetean, Zhongren Ding, and Satya P. Kunapuli

Department of Physiology, Temple University Medical School, Philadelphia, Pennsylvania 19140

Submitted 7 July 2003 ; accepted in final form 16 October 2003

Nucleotides are released during vascular injury from activated platelets and broken cells, which could stimulate human neutrophils. In this study, we characterized the P2Y receptors and investigated the functional effects of extracellular nucleotides on human neutrophils. Pharmacological characterization using selective agonists and pertussis toxin revealed that human neutrophils express only functional P2Y2 receptors. However, P2Y2 receptor agonists ATP or uridine triphosphate (UTP) caused intracellular Ca2+ increases in isolated human neutrophils with an EC50 of 1 µM but failed to cause release of primary granules from human neutrophils. ATP and UTP were equally potent in causing elastase release from human neutrophils in the presence of exogenous soluble fibrinogen, whereas ADP and UDP were without effect. We investigated whether nucleotides depend on generated arachidonic acid metabolites to cause degranulation. However, phenidone and MK-886, inhibitors of the 5-lipoxygenase pathway, failed to block nucleotide-induced intracellular calcium mobilization and elastase release. ATP and UTP caused activation of p38 MAPK and ERK1/2 in human neutrophils. In addition, the inhibitors of the MAPK pathway, SB-203580 and U-0126, inhibited nucleotide-induced elastase release. We conclude that fibrinogen is required for nucleotide-induced primary granule release from human neutrophils through the P2Y2 receptor without a role for arachidonic acid metabolites. Both ERK1/2 and p38 MAPK play an important role in nucleotide-induced primary granule release from human neutrophils.

elastase release; fibrinogen; extracellular nucleotides; uridine triphosphate; adenosine triphosphate


Address for reprint requests and other correspondence: S. P. Kunapuli, Dept. of Physiology, Temple Univ. Medical School, 3420 N. Broad St., Philadelphia, PA, 19140 (E-mail: spk{at}temple.edu).




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