Determination of PAR4 numbers on the surface of human platelets: no effect of the single nucleotide polymorphism rs773902

Simeng Li; Volga Tarlac; Roberto B.I. Christanto; Shauna L. French; Justin R. Hamilton

doi:10.1080/09537104.2020.1810654

Determination of PAR4 numbers on the surface of human platelets: no effect of the single nucleotide polymorphism rs773902

Simeng Li, Volga Tarlac, Roberto B.I. Christanto, Shauna L. French, Justin R. Hamilton

Australian Centre for Blood Diseases

Research output: Contribution to journal › Article › Research › peer-review

4 Citations (Scopus)

Abstract

The thrombin receptor, protease-activated receptor 4 (PAR4), is important for platelet activation and is the target of emerging anti-thrombotic drugs. A frequently occurring single nucleotide polymorphism (SNP; rs773902) causes a function-altering PAR4 sequence variant (NC_000019.10:p.Ala120Thr), whereby platelets from Thr120-expressing individuals are hyper-responsive to PAR4 agonists and hypo-responsive to some PAR4 antagonists than platelets from Ala120-expressing individuals. This altered pharmacology may impact PAR4 inhibitor development, yet the underlying mechanism(s) remain unknown. We tested whether PAR4 surface expression contributes to the altered receptor function. Quantitative flow cytometry was used to determine the absolute number of PAR4 on platelets from individuals subsequently genotyped at rs773902. We detected 539 ± 311 PAR4 per platelet (mean ± SD, n = 84). This number was not different across rs773902 genotypes. This first determination of cellular PAR4 numbers indicates variations in platelet surface expression do not explain the altered pharmacology of the rs773902 PAR4 sequence variant.

Original language	English
Pages (from-to)	988-991
Number of pages	4
Journal	Platelets
Volume	32
Issue number	7
DOIs	https://doi.org/10.1080/09537104.2020.1810654
Publication status	Published - 3 Oct 2021

Keywords

Platelets
protease-activated receptors
thrombin

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10.1080/09537104.2020.1810654

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title = "Determination of PAR4 numbers on the surface of human platelets: no effect of the single nucleotide polymorphism rs773902",

abstract = "The thrombin receptor, protease-activated receptor 4 (PAR4), is important for platelet activation and is the target of emerging anti-thrombotic drugs. A frequently occurring single nucleotide polymorphism (SNP; rs773902) causes a function-altering PAR4 sequence variant (NC_000019.10:p.Ala120Thr), whereby platelets from Thr120-expressing individuals are hyper-responsive to PAR4 agonists and hypo-responsive to some PAR4 antagonists than platelets from Ala120-expressing individuals. This altered pharmacology may impact PAR4 inhibitor development, yet the underlying mechanism(s) remain unknown. We tested whether PAR4 surface expression contributes to the altered receptor function. Quantitative flow cytometry was used to determine the absolute number of PAR4 on platelets from individuals subsequently genotyped at rs773902. We detected 539 ± 311 PAR4 per platelet (mean ± SD, n = 84). This number was not different across rs773902 genotypes. This first determination of cellular PAR4 numbers indicates variations in platelet surface expression do not explain the altered pharmacology of the rs773902 PAR4 sequence variant.",

keywords = "Platelets, protease-activated receptors, thrombin",

author = "Simeng Li and Volga Tarlac and Christanto, {Roberto B.I.} and French, {Shauna L.} and Hamilton, {Justin R.}",

year = "2021",

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doi = "10.1080/09537104.2020.1810654",

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AU - Li, Simeng

AU - Tarlac, Volga

AU - Christanto, Roberto B.I.

AU - French, Shauna L.

AU - Hamilton, Justin R.

PY - 2021/10/3

Y1 - 2021/10/3

N2 - The thrombin receptor, protease-activated receptor 4 (PAR4), is important for platelet activation and is the target of emerging anti-thrombotic drugs. A frequently occurring single nucleotide polymorphism (SNP; rs773902) causes a function-altering PAR4 sequence variant (NC_000019.10:p.Ala120Thr), whereby platelets from Thr120-expressing individuals are hyper-responsive to PAR4 agonists and hypo-responsive to some PAR4 antagonists than platelets from Ala120-expressing individuals. This altered pharmacology may impact PAR4 inhibitor development, yet the underlying mechanism(s) remain unknown. We tested whether PAR4 surface expression contributes to the altered receptor function. Quantitative flow cytometry was used to determine the absolute number of PAR4 on platelets from individuals subsequently genotyped at rs773902. We detected 539 ± 311 PAR4 per platelet (mean ± SD, n = 84). This number was not different across rs773902 genotypes. This first determination of cellular PAR4 numbers indicates variations in platelet surface expression do not explain the altered pharmacology of the rs773902 PAR4 sequence variant.

AB - The thrombin receptor, protease-activated receptor 4 (PAR4), is important for platelet activation and is the target of emerging anti-thrombotic drugs. A frequently occurring single nucleotide polymorphism (SNP; rs773902) causes a function-altering PAR4 sequence variant (NC_000019.10:p.Ala120Thr), whereby platelets from Thr120-expressing individuals are hyper-responsive to PAR4 agonists and hypo-responsive to some PAR4 antagonists than platelets from Ala120-expressing individuals. This altered pharmacology may impact PAR4 inhibitor development, yet the underlying mechanism(s) remain unknown. We tested whether PAR4 surface expression contributes to the altered receptor function. Quantitative flow cytometry was used to determine the absolute number of PAR4 on platelets from individuals subsequently genotyped at rs773902. We detected 539 ± 311 PAR4 per platelet (mean ± SD, n = 84). This number was not different across rs773902 genotypes. This first determination of cellular PAR4 numbers indicates variations in platelet surface expression do not explain the altered pharmacology of the rs773902 PAR4 sequence variant.

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Determination of PAR4 numbers on the surface of human platelets: no effect of the single nucleotide polymorphism rs773902

Abstract

Keywords

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Inhibition of the platelet thrombin receptor PAR4 to prevent thrombosis in coronary artery disease

Proof-of-concept studies for a novel anti-thrombotic agent

Cite this

Determination of PAR4 numbers on the surface of human platelets: no effect of the single nucleotide polymorphism rs773902

Abstract

Keywords

Access to Document

Other files and links

Projects

Inhibition of the platelet thrombin receptor PAR4 to prevent thrombosis in coronary artery disease

Proof-of-concept studies for a novel anti-thrombotic agent

Cite this