The NMDA receptor regulates integrin activation, ATP release and arterial thrombosis through store-operated Ca2+ entry in platelets
IntroductionPlatelet activation and thrombus formation is crucial for hemostasis, but also trigger arterial thrombosis. Calcium mobilization plays an important role in platelet activation, because many cellular processes depend on the level of intracellular Ca2+ ([Ca2+](i)), such as integrin activat...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1171831/full |
| _version_ | 1827949700009951232 |
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| author | Friedrich Reusswig Münteha Yilmaz Marius Brechtenkamp Irena Krueger Lisa Maria Metz Nikolaj Klöcker Eckhard Lammert Eckhard Lammert Eckhard Lammert Margitta Elvers |
| author_facet | Friedrich Reusswig Münteha Yilmaz Marius Brechtenkamp Irena Krueger Lisa Maria Metz Nikolaj Klöcker Eckhard Lammert Eckhard Lammert Eckhard Lammert Margitta Elvers |
| author_sort | Friedrich Reusswig |
| collection | DOAJ |
| description | IntroductionPlatelet activation and thrombus formation is crucial for hemostasis, but also trigger arterial thrombosis. Calcium mobilization plays an important role in platelet activation, because many cellular processes depend on the level of intracellular Ca2+ ([Ca2+](i)), such as integrin activation, degranulation, cytoskeletal reorganization. Different modulators of Ca2+ signaling have been implied, such as STIM1, Orai1, CyPA, SGK1, etc. Also, the N-methyl-D-aspartate receptor (NMDAR) was identified to contribute to Ca2+ signaling in platelets. However, the role of the NMDAR in thrombus formation is not well defined.MethodsIn vitro and in vivo analysis of platelet-specific NMDAR knock-out mice.ResultsIn this study, we analyzed Grin1fl/fl-Pf4-Cre+ mice with a platelet-specific knock-out of the essential GluN1 subunit of the NMDAR. We found reduced store-operated Ca2+ entry (SOCE), but unaltered store release in GluN1-deficient platelets. Defective SOCE resulted in reduced Src and PKC substrate phosphorylation following stimulation of glycoprotein (GP)VI or the thrombin receptor PAR4 followed by decreased integrin activation but unaltered degranulation. Consequently, thrombus formation on collagen under flow conditions was reduced ex vivo, and Grin1fl/fl-Pf4-Cre+ mice were protected against arterial thrombosis. Results from human platelets treated with the NMDAR antagonist MK-801 revealed a crucial role of the NMDAR in integrin activation and Ca2+ homeostasis in human platelets as well.ConclusionNMDAR signaling is important for SOCE in platelets and contributes to platelet activation and arterial thrombosis. Thus, the NMDAR represents a novel target for anti-platelet therapy in cardiovascular disease (CVD). |
| first_indexed | 2024-04-09T13:14:05Z |
| format | Article |
| id | doaj.art-fb4ddf7227b8408bae6d7481bb227b57 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-09T13:14:05Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-fb4ddf7227b8408bae6d7481bb227b572023-05-12T05:47:39ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-05-011010.3389/fcvm.2023.11718311171831The NMDA receptor regulates integrin activation, ATP release and arterial thrombosis through store-operated Ca2+ entry in plateletsFriedrich Reusswig0Münteha Yilmaz1Marius Brechtenkamp2Irena Krueger3Lisa Maria Metz4Nikolaj Klöcker5Eckhard Lammert6Eckhard Lammert7Eckhard Lammert8Margitta Elvers9Department of Vascular- and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Vascular- and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Vascular- and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Vascular- and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Vascular- and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, GermanyInstitute of Neural and Sensory Physiology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, GermanyInstitute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich-Heine University, Düsseldorf, GermanyGerman Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, Neuherberg, GermanyInstitute of Metabolic Physiology, Heinrich Heine University, Düsseldorf, GermanyDepartment of Vascular- and Endovascular Surgery, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, GermanyIntroductionPlatelet activation and thrombus formation is crucial for hemostasis, but also trigger arterial thrombosis. Calcium mobilization plays an important role in platelet activation, because many cellular processes depend on the level of intracellular Ca2+ ([Ca2+](i)), such as integrin activation, degranulation, cytoskeletal reorganization. Different modulators of Ca2+ signaling have been implied, such as STIM1, Orai1, CyPA, SGK1, etc. Also, the N-methyl-D-aspartate receptor (NMDAR) was identified to contribute to Ca2+ signaling in platelets. However, the role of the NMDAR in thrombus formation is not well defined.MethodsIn vitro and in vivo analysis of platelet-specific NMDAR knock-out mice.ResultsIn this study, we analyzed Grin1fl/fl-Pf4-Cre+ mice with a platelet-specific knock-out of the essential GluN1 subunit of the NMDAR. We found reduced store-operated Ca2+ entry (SOCE), but unaltered store release in GluN1-deficient platelets. Defective SOCE resulted in reduced Src and PKC substrate phosphorylation following stimulation of glycoprotein (GP)VI or the thrombin receptor PAR4 followed by decreased integrin activation but unaltered degranulation. Consequently, thrombus formation on collagen under flow conditions was reduced ex vivo, and Grin1fl/fl-Pf4-Cre+ mice were protected against arterial thrombosis. Results from human platelets treated with the NMDAR antagonist MK-801 revealed a crucial role of the NMDAR in integrin activation and Ca2+ homeostasis in human platelets as well.ConclusionNMDAR signaling is important for SOCE in platelets and contributes to platelet activation and arterial thrombosis. Thus, the NMDAR represents a novel target for anti-platelet therapy in cardiovascular disease (CVD).https://www.frontiersin.org/articles/10.3389/fcvm.2023.1171831/fullplateletsNMDARintegrinATPthrombosiscalcium |
| spellingShingle | Friedrich Reusswig Münteha Yilmaz Marius Brechtenkamp Irena Krueger Lisa Maria Metz Nikolaj Klöcker Eckhard Lammert Eckhard Lammert Eckhard Lammert Margitta Elvers The NMDA receptor regulates integrin activation, ATP release and arterial thrombosis through store-operated Ca2+ entry in platelets Frontiers in Cardiovascular Medicine platelets NMDAR integrin ATP thrombosis calcium |
| title | The NMDA receptor regulates integrin activation, ATP release and arterial thrombosis through store-operated Ca2+ entry in platelets |
| title_full | The NMDA receptor regulates integrin activation, ATP release and arterial thrombosis through store-operated Ca2+ entry in platelets |
| title_fullStr | The NMDA receptor regulates integrin activation, ATP release and arterial thrombosis through store-operated Ca2+ entry in platelets |
| title_full_unstemmed | The NMDA receptor regulates integrin activation, ATP release and arterial thrombosis through store-operated Ca2+ entry in platelets |
| title_short | The NMDA receptor regulates integrin activation, ATP release and arterial thrombosis through store-operated Ca2+ entry in platelets |
| title_sort | nmda receptor regulates integrin activation atp release and arterial thrombosis through store operated ca2 entry in platelets |
| topic | platelets NMDAR integrin ATP thrombosis calcium |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1171831/full |
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