Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors

Macwan, A. S., Boknas, N., Ntzouni, M. P., Ramstrom, S., Gibbins, J. M. ORCID: https://orcid.org/0000-0002-0372-5352, Faxalv, L. and Lindahl, T. L. (2019) Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors. Haematologica, 104 (7). pp. 1482-1492. ISSN 1592-8721 doi: 10.3324/haematol.2018.205815

Abstract/Summary

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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/81504
Identification Number/DOI	10.3324/haematol.2018.205815
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR) Life Sciences > School of Biological Sciences > Biomedical Sciences
Publisher	Ferrata Storti Foundation
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