The CalDAG-GEFI/Rap1/αIIbβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store-operated calcium entry
Circulating platelets maintain low cytosolic Ca2+ concentrations. At sites of vascular injury, agonist-induced Ca2+ release from platelet intracellular stores triggers influx of extracellular Ca2+, a process known as store-operated Ca2+ entry (SOCE). Stromal interaction molecule 1 (Stim1) senses red...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Platelets |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/09537104.2022.2157383 |
| _version_ | 1797684107103174656 |
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| author | Robert H. Lee David J. Rocco Bernhard Nieswandt Wolfgang Bergmeier |
| author_facet | Robert H. Lee David J. Rocco Bernhard Nieswandt Wolfgang Bergmeier |
| author_sort | Robert H. Lee |
| collection | DOAJ |
| description | Circulating platelets maintain low cytosolic Ca2+ concentrations. At sites of vascular injury, agonist-induced Ca2+ release from platelet intracellular stores triggers influx of extracellular Ca2+, a process known as store-operated Ca2+ entry (SOCE). Stromal interaction molecule 1 (Stim1) senses reduced Ca2+ stores and triggers SOCE. Gain-of-function (GOF) mutations in Stim1, such as described for Stormorken syndrome patients or mutant mice (Stim1Sax), are associated with marked thrombocytopenia and increased platelet turnover. We hypothesized that reduced platelet survival in Stim1Sax/+ mice is due to increased Rap1/integrin signaling and platelet clearance in the spleen, similar to what we recently described for mice expressing a mutant version of the Rap1-GAP, Rasa3 (Rasa3hlb/hlb). Stim1Sax/+ mice were crossed with mice deficient in CalDAG-GEFI, a critical calcium-regulated Rap1-GEF in platelets. In contrast to Rasa3hlb/hlb x Caldaggef1−/- mice, only a small increase in the peripheral platelet count, but not platelet lifespan, was observed in Stim1Sax/+ x Caldaggef1−/- mice. Similarly, inhibition of αIIbβ3 integrin in vivo only minimally raised the peripheral platelet count in Stim1Sax/+ mice. Compared to controls, Stim1Sax/+ mice exhibited increased platelet accumulation in the lung, but not the spleen or liver. These results suggest that CalDAG-GEFI/Rap1/integrin signaling contributes only minimally to accelerated platelet turnover caused by constitutive SOCE. |
| first_indexed | 2024-03-12T00:25:43Z |
| format | Article |
| id | doaj.art-f66e7dc148964a8e82a878d455bd4c95 |
| institution | Directory Open Access Journal |
| issn | 0953-7104 1369-1635 |
| language | English |
| last_indexed | 2024-03-12T00:25:43Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Platelets |
| spelling | doaj.art-f66e7dc148964a8e82a878d455bd4c952023-09-15T10:38:11ZengTaylor & Francis GroupPlatelets0953-71041369-16352023-12-0134110.1080/09537104.2022.21573832157383The CalDAG-GEFI/Rap1/αIIbβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store-operated calcium entryRobert H. Lee0David J. Rocco1Bernhard Nieswandt2Wolfgang Bergmeier3University of North CarolinaUniversity of North CarolinaUniversity Hospital WürzburgUniversity of North CarolinaCirculating platelets maintain low cytosolic Ca2+ concentrations. At sites of vascular injury, agonist-induced Ca2+ release from platelet intracellular stores triggers influx of extracellular Ca2+, a process known as store-operated Ca2+ entry (SOCE). Stromal interaction molecule 1 (Stim1) senses reduced Ca2+ stores and triggers SOCE. Gain-of-function (GOF) mutations in Stim1, such as described for Stormorken syndrome patients or mutant mice (Stim1Sax), are associated with marked thrombocytopenia and increased platelet turnover. We hypothesized that reduced platelet survival in Stim1Sax/+ mice is due to increased Rap1/integrin signaling and platelet clearance in the spleen, similar to what we recently described for mice expressing a mutant version of the Rap1-GAP, Rasa3 (Rasa3hlb/hlb). Stim1Sax/+ mice were crossed with mice deficient in CalDAG-GEFI, a critical calcium-regulated Rap1-GEF in platelets. In contrast to Rasa3hlb/hlb x Caldaggef1−/- mice, only a small increase in the peripheral platelet count, but not platelet lifespan, was observed in Stim1Sax/+ x Caldaggef1−/- mice. Similarly, inhibition of αIIbβ3 integrin in vivo only minimally raised the peripheral platelet count in Stim1Sax/+ mice. Compared to controls, Stim1Sax/+ mice exhibited increased platelet accumulation in the lung, but not the spleen or liver. These results suggest that CalDAG-GEFI/Rap1/integrin signaling contributes only minimally to accelerated platelet turnover caused by constitutive SOCE.http://dx.doi.org/10.1080/09537104.2022.2157383calciumplateletrap1stim1, thrombocytopenia |
| spellingShingle | Robert H. Lee David J. Rocco Bernhard Nieswandt Wolfgang Bergmeier The CalDAG-GEFI/Rap1/αIIbβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store-operated calcium entry Platelets calcium platelet rap1 stim1, thrombocytopenia |
| title | The CalDAG-GEFI/Rap1/αIIbβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store-operated calcium entry |
| title_full | The CalDAG-GEFI/Rap1/αIIbβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store-operated calcium entry |
| title_fullStr | The CalDAG-GEFI/Rap1/αIIbβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store-operated calcium entry |
| title_full_unstemmed | The CalDAG-GEFI/Rap1/αIIbβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store-operated calcium entry |
| title_short | The CalDAG-GEFI/Rap1/αIIbβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store-operated calcium entry |
| title_sort | caldag gefi rap1 αiibβ3 axis minimally contributes to accelerated platelet clearance in mice with constitutive store operated calcium entry |
| topic | calcium platelet rap1 stim1, thrombocytopenia |
| url | http://dx.doi.org/10.1080/09537104.2022.2157383 |
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