Differential role of protein kinase C delta isoform in agonist-induced dense granule secretion in human platelets.
Several platelet agonists, including thrombin, collagen, and thromboxane A(2), 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. PKCdelta 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 PKCdelta. SFLLRN- or AYPGKF-induced dense granule release and PKCdelta phosphorylation occurred at the same respective agonist concentration. Furthermore, AYPGKF and SFLLRN-induced dense granule release was blocked by rottlerin, a PKCdelta 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 PKCdelta has no role in platelet fibrinogen receptor activation. We conclude that PKCdelta and the classical PKC isoforms play a differential role in platelet dense granule release mediated by protease-activated receptors and glycoprotein VI. Furthermore, PKCdelta plays a positive role in protease-activated receptor-mediated dense granule secretion, whereas it functions as a negative regulator downstream of glycoprotein VI signaling.
Murugappan
Swaminathan
S
Departments of Physiology and Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Tuluc
Florin
F
Dorsam
Robert T
RT
Shankar
Haripriya
H
Kunapuli
Satya P
SP
D001792:Blood Platelets / Q000502:physiology*; D015550:Cell Degranulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011493:Protein Kinase C / Q000187:drug effects / Q000502:physiology*; D051745:Protein Kinase C-delta; D022142:Secretory Vesicles / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D007527:Isoenzymes; D009842:Oligopeptides; D010446:Peptide Fragments; D010980:Platelet Membrane Glycoproteins; C455901:alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine; C082835:thrombin receptor peptide (42-47); C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta