@article{Ankit S. Macwan_Niklas Boknäs_Maria P. Ntzouni_Sofia Ramström_Jonathan M. Gibbins_Lars Faxälv_Tomas L. Lindahl_2019, place={Pavia, Italy}, title={Gradient-dependent inhibition of stimulatory signaling from platelet G protein-coupled receptors}, volume={104}, url={https://haematologica.org/article/view/8978}, DOI={10.3324/haematol.2018.205815}, abstractNote={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 <em>per se</em&gt; 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.}, number={7}, journal={Haematologica}, author={Ankit S. Macwan and Niklas Boknäs and Maria P. Ntzouni and Sofia Ramström and Jonathan M. Gibbins and Lars Faxälv and Tomas L. Lindahl}, year={2019}, month={Jun.}, pages={1482-1492} }