Protein kinase Ctheta negatively regulates store-independent Ca2+ entry and phosphatidylserine exposure downstream of glycoprotein VI in platelets

MT Harper, AW Poole

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

26 Citations (Scopus)

Abstract

Platelet activation must be tightly controlled to provide an effective, but not excessive, response to vascular injury. Cytosolic calcium is a critical regulator of platelet function, including granule secretion, integrin activation, and phosphatidylserine (PS) exposure. Here we report that the novel protein kinase C isoform, PKCtheta, plays an important role in negatively regulating Ca(2+) signaling downstream of the major collagen receptor, glycoprotein VI (GPVI). This limits PS exposure and so may prevent excessive platelet procoagulant activity. Stimulation of GPVI resulted in significantly higher and more sustained Ca(2+) signals in PKCtheta(-/-) platelets. PKCtheta acts at multiple distinct sites. PKCtheta limits secretion, reducing autocrine ADP signaling that enhances Ca(2+) release from intracellular Ca(2+) stores. PKCtheta thereby indirectly regulates activation of store-operated Ca(2+) entry. However, PKCtheta also directly and negatively regulates store-independent Ca(2+) entry. This pathway, activated by the diacylglycerol analogue, 1-oleoyl-2-acetyl-sn-glycerol, was enhanced in PKCtheta(-/-) platelets, independently of ADP secretion. Moreover, LOE-908, which blocks 1-oleoyl-2-acetyl-sn-glycerol-induced Ca(2+) entry but not store-operated Ca(2+) entry, blocked the enhanced GPVI-dependent Ca(2+) signaling and PS exposure seen in PKCtheta(-/-) platelets. We propose that PKCtheta normally acts to restrict store-independent Ca(2+) entry during GPVI signaling, which results in reduced PS exposure, limiting platelet procoagulant activity during thrombus formation.
Translated title of the contributionProtein kinase Ctheta negatively regulates store-independent Ca2+ entry and phosphatidylserine exposure downstream of glycoprotein VI in platelets
Original languageEnglish
Pages (from-to)19865 - 19873
JournalJournal of Biological Chemistry
Volume285(26)
Publication statusPublished - Jun 2010

Bibliographical note

Author of Publication Reviewed: Harper MT, Poole AW

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