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J. Biol. Chem., Vol. 279, Issue 4, 2360-2367, January 23, 2004
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Differential Role of Protein Kinase C
Isoform in Agonist-induced Dense Granule Secretion in Human Platelets*
¶||¶**
From the
Departments of Physiology and ¶Pharmacology and the Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140
Several platelet agonists, including thrombin, collagen, and thromboxane A2, cause dense granule release independently of thromboxane generation. Because protein kinase C (PKC) isoforms are implicated in platelet secretion, we investigated the role of individual PKC isoforms in platelet dense granule release. PKC
was phosphorylated in a time-dependent manner that coincided with dense granule release in response to protease-activated receptor-activating peptides SFLLRN and AYPGKF in human platelets. Only agonists that caused platelet dense granule secretion activated PKC. SFLLRN- or AYPGKF-induced dense granule release and PKC phosphorylation occurred at the same respective agonist concentration. Furthermore, AYPGKF and SFLLRN-induced dense granule release was blocked by rottlerin, a PKC selective inhibitor. In contrast, convulxin-induced dense granule secretion was potentiated by rottlerin but was abolished by Go6976, a classical PKC isoform inhibitor. However, SFLLRN-induced dense granule release was unaffected in the presence of Go6976. Finally, rottlerin did not affect SFLLRN-induced platelet aggregation, even in the presence of dimethyl-BAPTA, indicating that PKC has no role in platelet fibrinogen receptor activation. We conclude that PKC and the classical PKC isoforms play a differential role in platelet dense granule release mediated by protease-activated receptors and glycoprotein VI. Furthermore, PKC plays a positive role in protease-activated receptor-mediated dense granule secretion, whereas it functions as a negative regulator downstream of glycoprotein VI signaling.
Received for publication, June 30, 2003 , and in revised form, September 26, 2003.
* This work was supported in part by National Institutes of Health Research Grants HL60683 and HL64943 (to S. P. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| Supported by National Institutes of Health Training Grant T32 HL07777.
** To whom correspondence should be addressed: Dept. of Physiology, Temple University, Rm. 224, OMS, 3420 N. Broad St., Philadelphia, PA 19140. Tel.: 215-707-4615; Fax: 215-707-4003; E-mail: spk{at}temple.edu.
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