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Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Hematology, Linköping University, Linköping, Sweden .
Core Facility, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.ORCID iD: 0000-0002-1920-3962
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2019 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 7Article in journal (Refereed) Published
Abstract [en]

As platelet activation is an irreversible and potentially harmful event, platelet stimulatory signaling must be tightly regulated to ensure the filtering-out of inconsequential fluctuations of agonist concentrations in the vascular milieu. Herein, we show that platelet activation via G protein-coupled receptors is gradient-dependent that is determined not only by agonist concentrations per se but also by how rapidly concentrations change over time. We demonstrate that gradient-dependent inhibition is a common feature of all major platelet stimulatory G protein-coupled receptors, while platelet activation via the non- G protein-coupled receptor glycoprotein VI is strictly concentration-dependent. By systematically characterizing the effects of variations in temporal agonist concentration gradients on different aspects of platelet activation, we demonstrate that gradient-dependent inhibition of protease-activated receptors exhibit different kinetics, with platelet activation occurring at lower agonist gradients for protease-activated receptor 4 than for protease-activated receptor 1, but share a characteristic bimodal effect distribution, as gradient-dependent inhibition increases over a narrow range of gradients, below which aggregation and granule secretion is effectively shut off. In contrast, the effects of gradient-dependent inhibition on platelet activation via adenosine diphosphate and thromboxane receptors increase incrementally over a large range of gradients. Further, depending on the affected activation pathway, gradient-dependent inhibition results in different degrees of refractoriness to subsequent autologous agonist stimulation. Mechanistically, our study identifies an important role for the cyclic adenosine monophosphate-dependent pathway in gradient-dependent inhibition. Together, our findings suggest that gradient-dependent inhibition may represent a new general mechanism for hemostatic regulation in platelets.

Place, publisher, year, edition, pages
Ferrata Storti Foundation, 2019. Vol. 104, no 7
Keywords [en]
Arterial Thrombosis, G protein coupled receptors, Platelets, Protease activated receptors
National Category
Pharmacology and Toxicology Hematology
Identifiers
URN: urn:nbn:se:oru:diva-71453DOI: 10.3324/haematol.2018.205815ISI: 000473230500037PubMedID: 30630981OAI: oai:DiVA.org:oru-71453DiVA, id: diva2:1279997
Funder
Swedish Heart Lung Foundation, 207-0440Swedish Research Council, 2017-01177
Note

Funding Agency:

British Heart Foundation  RG/15/2/31224

Available from: 2019-01-17 Created: 2019-01-17 Last updated: 2019-08-08Bibliographically approved

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Ramström, Sofia

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