TY - JOUR
T1 - Platelet calcium signaling by G-protein coupled and ITAM-linked receptors regulating anoctamin-6 and procoagulant activity
AU - Fernandez, Delia I.
AU - Kuijpers, Marijke J. E.
AU - Heemskerk, Johan W. M.
N1 - Funding Information:
DIF is supported by the H2020 Marie Skłodowska-Curie Actions agreement No. 766118 and is enrolled in a joint PhD program of the Universities of Maastricht (The Netherlands) and Santiago de Compostela (Spain).
Publisher Copyright:
© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.
PY - 2021/10/3
Y1 - 2021/10/3
N2 - Most agonists stimulate platelet Ca2+ rises via G-protein coupled receptors (GPCRs) or ITAM-linked receptors (ILRs). Well studied are the GPCRs stimulated by the soluble agonists thrombin (PAR1, PAR4), ADP (P2Y(1), P2Y(12)), and thromboxane A(2) (TP), signaling via phospholipase (PLC)beta isoforms. The platelet ILRs glycoprotein VI (GPVI), C-type lectin-like receptor 2 (CLEC2), and Fc gamma RIIa are stimulated by adhesive ligands or antibody complexes and signal via tyrosine protein kinases and PLC gamma isoforms. Marked differences exist between the GPCR- and ILR-induced Ca2+ signaling in: (i) dependency of tyrosine phosphorylation; (ii) oscillatory versus continued Ca2+ rises by mobilization from the endoplasmic reticulum; and (iii) smaller or larger role of extracellular Ca2+ entry via STIM1/ORAI1. Co-stimulation of both types of receptors, especially by thrombin (PAR1/4) and collagen (GPVI), leads to a highly enforced Ca2+ rise, involving mitochondrial Ca2+ release, which activates the ion and phospholipid channel, anoctamin-6. This highly Ca2+-dependent process causes swelling, ballooning, and phosphatidylserine expression, establishing a unique platelet population swinging between vital and necrotic (procoagulant 'zombie' platelets). Additionally, the high Ca2+ status of procoagulant platelets induces a set of additional events: (i) Ca2+ dependent cleavage of signaling proteins and receptors via calpain and ADAM isoforms; (ii) microvesiculation; (iii) enhanced coagulation factor binding; and (iv) fibrin-coat formation involving transglutaminases. Given the additive roles of GPCR and ILR in Ca2+ signal generation, high-throughput screening of biomolecules or small molecules based on Ca2+ flux measurements provides a promising way to find new inhibitors interfering with prolonged high Ca2+, phosphatidylserine expression, and hence platelet procoagulant activity.
AB - Most agonists stimulate platelet Ca2+ rises via G-protein coupled receptors (GPCRs) or ITAM-linked receptors (ILRs). Well studied are the GPCRs stimulated by the soluble agonists thrombin (PAR1, PAR4), ADP (P2Y(1), P2Y(12)), and thromboxane A(2) (TP), signaling via phospholipase (PLC)beta isoforms. The platelet ILRs glycoprotein VI (GPVI), C-type lectin-like receptor 2 (CLEC2), and Fc gamma RIIa are stimulated by adhesive ligands or antibody complexes and signal via tyrosine protein kinases and PLC gamma isoforms. Marked differences exist between the GPCR- and ILR-induced Ca2+ signaling in: (i) dependency of tyrosine phosphorylation; (ii) oscillatory versus continued Ca2+ rises by mobilization from the endoplasmic reticulum; and (iii) smaller or larger role of extracellular Ca2+ entry via STIM1/ORAI1. Co-stimulation of both types of receptors, especially by thrombin (PAR1/4) and collagen (GPVI), leads to a highly enforced Ca2+ rise, involving mitochondrial Ca2+ release, which activates the ion and phospholipid channel, anoctamin-6. This highly Ca2+-dependent process causes swelling, ballooning, and phosphatidylserine expression, establishing a unique platelet population swinging between vital and necrotic (procoagulant 'zombie' platelets). Additionally, the high Ca2+ status of procoagulant platelets induces a set of additional events: (i) Ca2+ dependent cleavage of signaling proteins and receptors via calpain and ADAM isoforms; (ii) microvesiculation; (iii) enhanced coagulation factor binding; and (iv) fibrin-coat formation involving transglutaminases. Given the additive roles of GPCR and ILR in Ca2+ signal generation, high-throughput screening of biomolecules or small molecules based on Ca2+ flux measurements provides a promising way to find new inhibitors interfering with prolonged high Ca2+, phosphatidylserine expression, and hence platelet procoagulant activity.
KW - Calcium channels
KW - glycoprotein VI
KW - GPCR
KW - thrombin
KW - TMEM16F
U2 - 10.1080/09537104.2020.1859103
DO - 10.1080/09537104.2020.1859103
M3 - Article
C2 - 33356720
SN - 0953-7104
VL - 32
SP - 863
EP - 871
JO - Platelets
JF - Platelets
IS - 7
ER -