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Delineating zinc influx mechanisms during platelet activation

Kuravi, S. J., Ahmed, N. S., Taylor, K. A. ORCID:, Capes, E. M., Bye, A. ORCID:, Unsworth, A. J., Gibbins, J. M. ORCID: and Pugh, N. (2023) Delineating zinc influx mechanisms during platelet activation. International Journal of Molecular Sciences, 24 (14). 11689. ISSN 1422-0067

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To link to this item DOI: 10.3390/ijms241411689


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
Divisions:Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:112712
Uncontrolled Keywords:Zinc, zinc entry, platelets, zinc induced platelet activation, aggregation, cation signalling, TRP channels, NCX, ZIP7, store-operate calcium entry, store-operated zinc entry


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