Functional divergence of platelet protein kinase C (PKC) isoforms in thrombus formation on collagen

Karen Gilio, Matthew T Harper, Judith M E M Cosemans, Olga Konopatskaya, Imke C A Munnix, Lenneke Prinzen, Michael Leitges, Qinghang Liu, Jeffery D Molkentin, Johan W M Heemskerk, Alastair W Poole

Research output: Contribution to journalArticle (Academic Journal)peer-review

77 Citations (Scopus)

Abstract

Arterial thrombosis, a major cause of myocardial infarction and stroke, is initiated by activation of blood platelets by subendothelial collagen. The protein kinase C (PKC) family centrally regulates platelet activation, and it is becoming clear that the individual PKC isoforms play distinct roles, some of which oppose each other. Here, for the first time, we address all four of the major platelet-expressed PKC isoforms, determining their comparative roles in regulating platelet adhesion to collagen and their subsequent activation under physiological flow conditions. Using mouse gene knock-out and pharmacological approaches in human platelets, we show that collagen-dependent alpha-granule secretion and thrombus formation are mediated by the conventional PKC isoforms, PKCalpha and PKCbeta, whereas the novel isoform, PKC, negatively regulates these events. PKCdelta also negatively regulates thrombus formation but not alpha-granule secretion. In addition, we demonstrate for the first time that individual PKC isoforms differentially regulate platelet calcium signaling and exposure of phosphatidylserine under flow. Although platelet deficient in PKCalpha or PKCbeta showed reduced calcium signaling and phosphatidylserine exposure, these responses were enhanced in the absence of PKC. In summary therefore, this direct comparison between individual subtypes of PKC, by standardized methodology under flow conditions, reveals that the four major PKCs expressed in platelets play distinct non-redundant roles, where conventional PKCs promote and novel PKCs inhibit thrombus formation on collagen.
Translated title of the contributionFunctional divergence of platelet protein kinase C (PKC) isoforms in thrombus formation on collagen
Original languageEnglish
Pages (from-to)23410 - 23419
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number30
Early online date17 May 2010
DOIs
Publication statusPublished - 23 Jul 2010

Bibliographical note

Author of Publication Reviewed: Gilio K, Harper MT, Cosemans JM, Konopatskaya O, Munnix IC, Prinzen L, Leitges M, Liu Q, Molkentin JD, Heemskerk JW, Poole AW

Keywords

  • Animals
  • Blood Platelets
  • Anticoagulants
  • Humans
  • Isoenzymes
  • Platelet Activation
  • Mice
  • Protein Kinase C
  • Platelet Membrane Glycoproteins
  • Thrombosis
  • Calcium Signaling
  • Collagen

Fingerprint Dive into the research topics of 'Functional divergence of platelet protein kinase C (PKC) isoforms in thrombus formation on collagen'. Together they form a unique fingerprint.

Cite this