Protease-activated receptor-4 (PAR4) variant influences on platelet reactivity induced by PAR4-activating peptide through altered Ca2+ mobilization and ERK phosphorylation in healthy Japanese subjects

Thrombosis Research
Yoichiro MorikawaYoshiaki Tomiyama

Abstract

Thrombin belongs to the most potent platelet agonists and activates human platelets through GPIbα and two protease activated receptors (PARs), PAR1 and PAR4. However, the details of thrombin receptor system, especially the role of PAR4 on human platelet activation is still not clear. We found a significant difference in PAR4-activating peptide (PAR4-AP)-induced, but not PAR1-AP, platelet aggregation between healthy Japanese subjects. Sequencing analysis revealed a single nucleotide change in PAR4 gene F2RL3 (SNP rs773902) leading to Ala120Thr variant. To elucidate the role of PAR4 in human platelet activation, we examined if platelet activation induced by PAR4-AP may be associated with PAR4 genotype. Platelets from 202 healthy Japanese volunteers were genetically analyzed and determined the genotype frequency of rs773902. Agonist induced platelet aggregation, integrin αIIbβ3 activation, granule release, Ca2+ mobilization, and activation of ERK and MLC were evaluated. The specificity of effects observed in platelets was confirmed in 293T cells transfected PAR4-Thr120 or Ala120. The frequencies of PAR4 variant Thr/Thr120, Ala/Thr120, and Ala/Ala 120 were 5.9, 37.1, and 57.0%, respectively. Platelets with Thr/Thr120 showed signifi...Continue Reading

Citations

Jun 13, 2020·Platelets·Fawaz O Alenazy, Mark R Thomas
Nov 14, 2019·International Journal of Molecular Sciences·Simeng LiJustin R Hamilton
Dec 29, 2020·Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association·Asami KamadaYasuo Terayama
Mar 27, 2021·Thrombosis Research·Shaji AbrahamSteven E McKenzie
Aug 28, 2020·Thrombosis Research·Xu Han, Marvin T Nieman
Sep 29, 2019·Peptides·Xavier MataCatherine Mollereau

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