Evidence that Inositol-1,4,5-trisphosphate-3-kinase and Inositol-1,3,4,5-tetrakisphosphate are negative regulators of platelet function

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Authi, K. S., Khan, S., Gibbins, J. ORCID: https://orcid.org/0000-0002-0372-5352 and Brain, S. D. (2024) Evidence that Inositol-1,4,5-trisphosphate-3-kinase and Inositol-1,3,4,5-tetrakisphosphate are negative regulators of platelet function. Research and Practice in Thrombosis and Haemostasis. ISSN 2475-0379 (In Press)

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Abstract/Summary

Inositol-1,3,4,5-tetrakisphosphate (IP4) is formed from inositol-1,4,5-trisphosphate (IP3) by IP3-3 kinase (ITPK) in most cells. Its function is unknown but has been suggested to be involved in Ca2+ entry, IP3 regulation and phosphoinositide 3-kinase antagonism. Objectives. To better elucidate a function for IP4 we tested a specific inhibitor of ITPK (GNF362) on platelets, the effects of IP4 directly in permeabilised platelets and its effect on PIP3 binding to pleckstrin-homology (PH) domain containing proteins in platelets. Methods. Human platelets were utilised in whole blood for thrombus formation, in platelet rich plasma and washed suspensions for aggregation, Ca2+ studies, or resuspended in higher K+ and low Na+ buffers for permeabilization experiments. Phosphorylation of AKT-Ser473 and Rap1-GTP formation were measured by Western blotting and PIP3 binding using PIP3 beads. Results. GNF362 enhanced platelet aggregation stimulated by low concentrations of ADP, collagen, thrombin, U46619 and thrombus formation in collagen coated capillaries. GNF362 induced a transient elevation of Ca2+, elevated basal levels of IP3 and enhanced the peak height of Ca2+ elevated by agonists. In permeabilised platelets, IP4 inhibited GTPγS induced formation of AKT-Ser473 phosphorylation and platelet aggregation. IP4 reduced GTPγS stimulated Rap1-GTP levels and potently reduced extraction of RASA3 and BTK by PIP3 beads. Conclusion. ITPK and IP4 are negative regulators of platelet function. IP4 regulation of PH domain containing proteins may represent a pathway by which platelet activation may be controlled during thrombosis.

Item Type:	Article
Refereed:	Yes
Divisions:	Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR) Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:	114606
Uncontrolled Keywords:	Inositol-1,3,4,5-tetrakisphosphate, inositol-1,4,5-trisphosphate-3-kinase, platelet activation, phosphoinositide 3-kinase, phosphatidylinositol-3,4,5-trisphosphate.
Publisher:	Elsevier

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References

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Evidence that Inositol-1,4,5-trisphosphate-3-kinase and Inositol-1,3,4,5-tetrakisphosphate are negative regulators of platelet function

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