Delineating zinc influx mechanisms during platelet activation

Kuravi, S. J., Ahmed, N. S., Taylor, K. A. ORCID: https://orcid.org/0000-0002-4599-7727, Capes, E. M., Bye, A. ORCID: https://orcid.org/0000-0002-2061-2253, Unsworth, A. J., Gibbins, J. M. ORCID: https://orcid.org/0000-0002-0372-5352 and Pugh, N. (2023) Delineating zinc influx mechanisms during platelet activation. International Journal of Molecular Sciences, 24 (14). 11689. ISSN 1661-6596 doi: 10.3390/ijms241411689

Abstract/Summary

Zinc (Zn2+) is released by platelets during the haemostatic response to injury. Extracellular zinc ([Zn2+]o) initiates platelet activation following influx into the platelet cytosol. However, the mechanisms which permit Zn2+ influx are unknown. Fluctuations in intracellular zinc ([Zn2+]i) were measured in fluozin-3-loaded platelets using fluorometry and flow cytometry. Platelet ac-tivation was assessed using light transmission aggregometry. Detection of phosphoproteins was performed by Western blotting. [Zn2+]o influx and subsequent platelet activation was abrogated by blocking the sodium-calcium exchanger, TRP channels and ZIP7. Cation store depletion regu-lated Zn2+ influx. [Zn2+]o stimulation resulted in phosphorylation of PKC substates, MLC, and the β3 integrin. Platelet activation via GPVI or Zn2+ resulted in ZIP7 phosphorylation in a casein ki-nase 2 dependent manner, and initiated elevations of [Zn2+]i that were sensitive to inhibition of Orai1, ZIP7, or IP3R-mediated pathways. These data indicate that platelets detect and respond to changes in [Zn2+]o via influx into the cytosol through TRP channels and NCX exchanger. Platelet activation results in externalisation of ZIP7 which further regulates Zn2+ influx. Increases in [Zn2+]i contribute to the activation of cation-dependent enzymes. Sensitivity of Zn2+ influx to thapsigargin indicates a store-operated pathway that we term store-operated Zn2+ entry (SOZE). These mechanisms may affect platelet behaviour during thrombosis and haemostasis.

Item Type	Article
URI	https://reading-pure-test.eprints-hosting.org/id/eprint/112712
Identification Number/DOI	10.3390/ijms241411689
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy Central Services
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