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 Ca concentrations. At sites of vascular injury, agonist-induced Ca release from platelet intracellular stores triggers influx of extracellular Ca , a process known as store-operated Ca entry (SOCE). Stromal interaction molecule 1 (Stim1) senses reduced Ca stores and triggers SOCE. Gain-of-function (GOF) mutations in Stim1, such as described for Stormorken syndrome patients or mutant mice ( ), are associated with marked thrombocytopenia and increased platelet turnover. We hypothesized that reduced platelet survival in 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 ( ). mice were crossed with mice deficient in CalDAG-GEFI, a critical calcium-regulated Rap1-GEF in platelets. In contrast to mice, only a small increase in the peripheral platelet count, but not platelet lifespan, was observed in mice. Similarly, inhibition of αIIbβ3 integrin in vivo only minimally raised the peripheral platelet count in mice. Compared to controls, 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.