biostudies-literatureZou JChina Scholarship CouncilCentral People's Government of the People's Republic of China Scholarship ProgrammeEuropean Research CouncilHorizon 2020 Framework Programme107899https://www.ebi.ac.uk/biostudies/studies/S-EPMC11742345biostudies-literatureUnknown300(12)Agonist-induced rises in cytosolic Ca²⁺ control most platelet responses in thrombosis and hemostasis. In human platelets, we earlier demonstrated that the ORAI1-STIM1 pathway is a major component of extracellular Ca²⁺ entry, in particular when induced via the ITAM-linked collagen receptor, glycoprotein VI (GPVI). In the present article, using functionally defective platelets from patients with a loss-of-function mutation in ORAI1 or STIM1, we show that Ca²⁺ entry induced by the endoplasmic reticulum ATPase inhibitor, thapsigargin, fully relies on this pathway. We demonstrate that both the GPVI-induced and thapsigargin-induced Ca²⁺ entry are strongly suppressed by protein kinase C (PKC) activation while leaving intracellular Ca²⁺ mobiliThe Journal of biological chemistrySuppressed ORAI1-STIM1-dependent Ca<sup>2+</sup> entry by protein kinase C isoforms regulating platelet procoagulant activity.PMC11742345813409201909370052Provenzale IZou JSolari FAJurk KKuijpers MJESickmann AZieger BZhang PSwieringa FMattheij NJASchonichen CRauch JSHeemskerk JWMfalseSuppressed ORAI1-STIM1-dependent Ca<sup>2+</sup> entry by protein kinase C isoforms regulating platelet procoagulant activity.Agonist-induced rises in cytosolic Ca²⁺ control most platelet responses in thrombosis and hemostasis. In human platelets, we earlier demonstrated that the ORAI1-STIM1 pathway is a major component of extracellular Ca²⁺ entry, in particular when induced via the ITAM-linked collagen receptor, glycoprotein VI (GPVI). In the present article, using functionally defective platelets from patients with a loss-of-function mutation in ORAI1 or STIM1, we show that Ca²⁺ entry induced by the endoplasmic reticulum ATPase inhibitor, thapsigargin, fully relies on this pathway. We demonstrate that both the GPVI-induced and thapsigargin-induced Ca²⁺ entry are strongly suppressed by protein kinase C (PKC) activation while leaving intracellular Ca²⁺ mobili2024-01-01T00:00:00Z2024 Dec2025-04-22T05:22:37.512Z2025-04-05T21:19:35.243ZS-EPMC117423453942414510.1016/j.jbc.2024.107899