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Rapid activation of platelets calday sites of vascular injury is a critical event in thrombosis and hemostasis. The regulated activation of platelets is an essential component of thrombosis and hemostasis. DAG is critical for protein kinase C PKC activation, a key event in platelet granule release and integrin activation [ 1 ]. CalDAG-GEFI activates the small GTPase Rap1, a central molecular switch that drives platelet activation by directly regulating integrin-mediated aggregation [ 2634 ] and the release of autocrine agonists [ caodag ].

It is a member of the RasGRP family that includes four guanine nucleotide exchange factors, which differ for tissue expression and target specifity A, table. CalDAG-GEFI amino acids is predominantly expressed in the brain [ 7 ] and, within the hematopoietic lineage, in megakaryocytes and platelets as well as neutrophils [ 2 ]. A longer CalDAG-GEFI splice variant 62 additional N-terminal residues with a different substrate specificity and a different intracellular localization has been proposed, [ 8 ] but the endogenous version has not been identified.

It specifically activates Rap1 and Rap2 but lacks Ras exchange activity in vivo [ 7 ]. The C1 domain sequence is atypical and shows only weak affinity for DAG.


CalDAG-GEFI and platelet activation

Most of the later studies have been performed in a knockout mouse model, which has confirmed the importance of CalDAG-GEFI in Rap1 and integrin activation in both platelets [ 2 ] [ 16 ] and neutrophils [ 3 ] B, lower panel. The two Rap1 activation pathways have complementary kinetics and fulfill different roles in thrombus growth.

The results from these studies are summarized schematically in section D of figure 1.

The key elements of this model are: D Schematic model of platelet activation over time upon stimulation with thrombin upper panel or collagen lower panel. The importance of CalDAG-GEFI signaling for platelet function was emphasized in experiments performed under physiological flow conditions both in vitro and in vivo.

CalDAG-GEFI-deficient mice also had problems to maintain hemostasis when challenged, with tail bleeding times being similar to those observed in wild-type mice treated with the P2Y12 inhibitor clopidogrel E, lower right panel. Due to their defect in the rapid activation of Rap1, CalDAG-GEFI-deficient platelets may not be able to activate their integrins fast enough to allow adhesion under conditions of high shear stress.

Supporting this idea, we 209 the most striking defects in the adhesion of CalDAG-GEFI-deficient neutrophils in vivo rather than under static conditions in vitro [ 3 ].

Since the brain is also largely protected from drugs by the blood-brain-barrier, inhibition of neutrophil function will be the 20009 likely side-effect of targeting CalDAG-GEFI in platelets. Importantly, studies in dogs with naturally occurring mutations in CalDAG-GEFI confirmed its central role in platelet activation, while no defects in neutrophil function were reported [ 21 ].


CalDAG California Disabled Accessibility Guidebook An Interpretive Manual and Checklist

National Center for Biotechnology InformationU. Author manuscript; available in PMC Aug 3. Lucia Stefanini and Wolfgang Bergmeier. Author information Copyright and License information Disclaimer.

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The publisher’s final edited version of this article is available at Platelets. See other articles in PMC that cite the published article. Abstract Rapid activation of platelets at sites of vascular injury is a critical event in thrombosis and hemostasis. Introduction The regulated activation of platelets is an essential component of thrombosis and hemostasis.

Open in a separate window. Diverse functions of protein kinase C isoforms in platelet activation and thrombus formation. Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3. A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs.

Epac1-Rap1 signaling regulates monocyte adhesion and chemotaxis. Calcium-diacylglycerol guanine nucleotide exchange factor I gene mutations associated with loss of function in canine platelets. Support Center Support Center. Please review our privacy policy.