Evidence map›Paper›PMID 27784794›Full record

ArticleMolecular pharmacology2017

Contributions of Protease-Activated Receptors PAR1 and PAR4 to Thrombin-Induced GPIIbIIIa Activation in Human Platelets.

Matthew T Duvernay, Kayla J Temple, Jae G Maeng, Anna L Blobaum, Shaun R Stauffer, Craig W Lindsley, Heidi E Hamm

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.

0numbers the graph read from it
0cells of the map it votes in
21citing papers in PubMed
2.0field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

21 citing papers in PubMed, 43 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Review
  5. Article
  6. Article
  7. Article
  8. Microvascular Thrombosis as a Critical Factor in Severe COVID-19.International journal of molecular sciences · 2023
    Article
  9. Review
  10. Protease-activated receptor-mediated platelet aggregation in patients with type 2 diabetes on potent P2YDiabetic medicine : a journal of the British Diabetic Association · 2022
    Article
  11. Article
  12. Article
  13. Article
  14. Article
  15. Review
  16. Observational
  17. The "Janus Face" of Platelets in Cancer.International journal of molecular sciences · 2020
    Review
  18. Article
  19. The role of coagulation and platelets in colon cancer-associated thrombosis.American journal of physiology. Cell physiology · 2019
    Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 2 institutions in 1 country.

Matthew T DuvernayDepartment of Pharmacology (M.T.D., K.J.T., J.G.M., A.L.B., S.R.S., C.W.L., H.E.H.) and Vanderbilt Center for Neuroscience Drug Discovery (K.J.T., A.L.B., S.R.S., C.W.L.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Chemistry, Vanderbilt University, Nashville, Tennessee (S.R.S., C.W.L.).
Kayla J TempleDepartment of Pharmacology (M.T.D., K.J.T., J.G.M., A.L.B., S.R.S., C.W.L., H.E.H.) and Vanderbilt Center for Neuroscience Drug Discovery (K.J.T., A.L.B., S.R.S., C.W.L.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Chemistry, Vanderbilt University, Nashville, Tennessee (S.R.S., C.W.L.).
Jae G MaengDepartment of Pharmacology (M.T.D., K.J.T., J.G.M., A.L.B., S.R.S., C.W.L., H.E.H.) and Vanderbilt Center for Neuroscience Drug Discovery (K.J.T., A.L.B., S.R.S., C.W.L.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Chemistry, Vanderbilt University, Nashville, Tennessee (S.R.S., C.W.L.).
Anna L BlobaumDepartment of Pharmacology (M.T.D., K.J.T., J.G.M., A.L.B., S.R.S., C.W.L., H.E.H.) and Vanderbilt Center for Neuroscience Drug Discovery (K.J.T., A.L.B., S.R.S., C.W.L.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Chemistry, Vanderbilt University, Nashville, Tennessee (S.R.S., C.W.L.).
Shaun R StaufferDepartment of Pharmacology (M.T.D., K.J.T., J.G.M., A.L.B., S.R.S., C.W.L., H.E.H.) and Vanderbilt Center for Neuroscience Drug Discovery (K.J.T., A.L.B., S.R.S., C.W.L.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Chemistry, Vanderbilt University, Nashville, Tennessee (S.R.S., C.W.L.).
Craig W LindsleyDepartment of Pharmacology (M.T.D., K.J.T., J.G.M., A.L.B., S.R.S., C.W.L., H.E.H.) and Vanderbilt Center for Neuroscience Drug Discovery (K.J.T., A.L.B., S.R.S., C.W.L.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Chemistry, Vanderbilt University, Nashville, Tennessee (S.R.S., C.W.L.).
Heidi E HammDepartment of Pharmacology (M.T.D., K.J.T., J.G.M., A.L.B., S.R.S., C.W.L., H.E.H.) and Vanderbilt Center for Neuroscience Drug Discovery (K.J.T., A.L.B., S.R.S., C.W.L.), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Chemistry, Vanderbilt University, Nashville, Tennessee (S.R.S., C.W.L.) heidi.hamm@vanderbilt.edu.
Vanderbilt University Medical Center · USVanderbilt University · US

Funding

Optimization of PAR4 antagonists for thrombotic disordersR01NS081669 · NINDS · VANDERBILT UNIVERSITY · PI HAMM, HEIDI E · 2013 to 2015
$1.0M
Screening for allosteric modulators of the protease activated receptor 4R01NS082198 · NINDS · VANDERBILT UNIVERSITY · PI HAMM, HEIDI E · 2013 to 2015
$1.0M
NINDS NIH HHS R01 NS081669NINDS NIH HHS R01 NS082198
6 · The paper itself

Abstract

Human platelets display a unique dual receptor system for responding to its primary endogenous activator, α-thrombin. Because of the lack of efficacious antagonists, the field has relied on synthetic peptides and pepducins to describe protease-activated receptor PAR1 and PAR4 signaling. The precise contributions of each receptor have not been established in the context of thrombin. We took advantage of newly discovered PAR antagonists to contrast the contribution of PAR1 and PAR4 to thrombin-mediated activation of the platelet fibrin receptor (GPIIbIIIa). PAR1 is required for platelet activation at low but not high concentrations of thrombin, and maximal platelet activation at high concentrations of thrombin requires PAR4. As the concentration of thrombin is increased, PAR1 signaling is quickly overcome by PAR4 signaling, leaving a narrow window of low thrombin concentrations that exclusively engage PAR1. PAR4 antagonism reduces the maximum thrombin response by over 50%. Thus, although the PAR1 response still active at higher concentrations of thrombin, this response is superseded by PAR4. Truncation of a known PAR4 antagonist and identification of the minimum pharmacophore converted the mechanism of inhibition from noncompetitive to competitive, such that the antagonist could be outcompeted by increasing doses of the ligand. Fragments retained efficacy against both soluble and tethered ligands with lower cLogP values and an increased free fraction in plasma. These reversible, competitive compounds represent a route toward potentially safer PAR4 antagonists for clinical utility and the development of tools such as radioligands and positron emission tomography tracers that are not currently available to the field for this target.

Indexed as

Blood PlateletsHumansIntegrin beta3LigandsPlatelet Aggregation InhibitorsPlatelet Glycoprotein GPIb-IX ComplexReceptor, PAR-1Receptors, ThrombinSignal TransductionThrombinglycoprotein receptor GPIb-IXIntegrin beta3LigandsPlatelet Aggregation InhibitorsPlatelet Glycoprotein GPIb-IX Complexprotease-activated receptor 4Receptor, PAR-1Receptors, ThrombinThrombin

Identifiers

PMID27784794
PMCPMC5198515
OpenAlexW2557337009

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.