title: Zinc is a transmembrane agonist that induces platelet activation in a tyrosine phosphorylation-dependent manner.
abstract: Following platelet adhesion and primary activation at sites of vascular injury, secondary platelet activation is induced by soluble platelet agonists, such as ADP, ATP, thrombin and thromboxane. Zinc ions are also released from platelets and damaged cells and have been shown to act as a platelet agonist. However, the mechanism of zinc-induced platelet activation is not well understood. Here we show that exogenous zinc gains access to the platelet cytosol and induces full platelet aggregation that is dependent on platelet protein tyrosine phosphorylation, PKC and integrin αIIbβ3 activity and is mediated by granule release and secondary signalling. ZnSO4 increased the binding affinity of GpVI, but not integrin α2β1. Low concentrations of ZnSO4 potentiated platelet aggregation by collagen-related peptide (CRP-XL), thrombin and adrenaline. Chelation of intracellular zinc reduced platelet aggregation induced by a number of different agonists, inhibited zinc-induced tyrosine phosphorylation and inhibited platelet activation in whole blood under physiologically relevant flow conditions. Our data are consistent with a transmembrane signalling role for zinc in platelet activation during thrombus formation.
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, UK.
authors.forename: Ben R
authors.initials: BR
authors.lastname: Watson
authors.affiliation: Department of Biomedical and Forensic Sciences, Anglia Ruskin University, East Road, Cambridge, UK. nicholas.pugh@anglia.ac.uk.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: White
authors.affiliation: Department of Biomedical and Forensic Sciences, Anglia Ruskin University, East Road, Cambridge, UK. nicholas.pugh@anglia.ac.uk.
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, UK.
authors.forename: Joanna-Marie
authors.initials: JM
authors.lastname: Howes
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, UK.
authors.forename: Jean-Daniel M
authors.initials: JD
authors.lastname: Malcor
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, UK.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bihan
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK.
authors.forename: Stewart O
authors.initials: SO
authors.lastname: Sage
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, UK.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Farndale
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, UK and Department of Biomedical and Forensic Sciences, Anglia Ruskin University, East Road, Cambridge, UK. nicholas.pugh@anglia.ac.uk.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pugh
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D006801:Humans; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001798:Blood Proteins; D002352:Carrier Proteins; D005029:Ethylenediamines; D010455:Peptides; D010980:Platelet Membrane Glycoproteins; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; D019000:Phosphotyrosine; D013917:Thrombin; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D004837:Epinephrine