Abstract
PI3KC2α is a broadly expressed lipid kinase with critical functions during embryonic development but poorly defined roles in adult physiology. Here we utilize multiple mouse genetic models to uncover a role for PI3KC2α in regulating the internal membrane reserve structure of megakaryocytes (demarcation membrane system) and platelets (open canalicular system) that results in dysregulated platelet adhesion under haemodynamic shear stress. Structural alterations in the platelet internal membrane lead to enhanced membrane tether formation that is associated with accelerated, yet highly unstable, thrombus formation in vitro and in vivo. Notably, agonist-induced 3-phosphorylated phosphoinositide production and cellular activation are normal in PI3KC2α-deficient platelets. These findings demonstrate an important role for PI3KC2α in regulating shear-dependent platelet adhesion via regulation of membrane structure, rather than acute signalling. These studies provide a link between the open canalicular system and platelet adhesive function that has relevance to the primary haemostatic and prothrombotic function of platelets.
Highlights
PI3KC2a is a broadly expressed lipid kinase with critical functions during embryonic development but poorly defined roles in adult physiology
We generate a series of new genetic mouse models in which PI3KC2a is markedly reduced and observe that altered structure of the demarcation membrane system (DMS) of PI3KC2a-deficient megakaryocytes does not impact on quantitative platelet production, but that altered structure of the platelet OCS leads to dysregulated platelet adhesion and the consequent formation of large, unstable platelet thrombi
While we have shown that PI3KC2b is the major class II Phosphoinositide 3-kinases (PI3Ks) isoform expressed in platelets, no significant function of this enzyme was detected in these cells
Summary
PI3KC2a is a broadly expressed lipid kinase with critical functions during embryonic development but poorly defined roles in adult physiology. The internal membrane reserves of the platelet, known as the surface-connected OCS, consists of a network of membrane-bound cisternae and tubules[27] It is a dominant ultrastructural feature of the cell and plays a key role in the morphological changes critical for platelet function We generate a series of new genetic mouse models in which PI3KC2a is markedly reduced and observe that altered structure of the demarcation membrane system (DMS) of PI3KC2a-deficient megakaryocytes does not impact on quantitative platelet production, but that altered structure of the platelet OCS leads to dysregulated platelet adhesion and the consequent formation of large, unstable platelet thrombi These studies define an unexpected role for PI3KC2a in regulating the structure of the platelet internal membranes, and provide the first evidence linking the OCS to the haemostatic and prothrombotic function of platelets
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