Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptorsShow others and affiliations
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, i.e., 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 exhibits different kinetics, with platelet activation occurring at lower agonist gradients for protease-activated receptor 4 than for protease-activated receptor 1, but shares 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. Furthermore, 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
National Category
Hematology
Identifiers
URN: urn:nbn:se:liu:diva-158960DOI: 10.3324/haematol.2018.205815ISI: 000473230500037PubMedID: 30630981OAI: oai:DiVA.org:liu-158960DiVA, id: diva2:1338150
Note
Funding Agencies|Swedish Heart-Lung Foundation [207-0440]; Swedish Research Council [2017-01177]; British Heart Foundation [RG/15/2/31224]
2019-07-192019-07-192019-11-12