TY - JOUR AU - Ankit S. Macwan, AU - Niklas Boknäs, AU - Maria P. Ntzouni, AU - Sofia Ramström, AU - Jonathan M. Gibbins, AU - Lars Faxälv, AU - Tomas L. Lindahl, PY - 2019/06/30 Y2 - 2024/03/28 TI - Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors JF - Haematologica JA - haematol VL - 104 IS - 7 SE - Articles DO - 10.3324/haematol.2018.205815 UR - https://haematologica.org/article/view/8978 SP - 1482-1492 AB - 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. ER -