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Lysophosphatidic Acid-Activated Calcium Signaling Is Elevated in Red Cells from Sickle Cell Disease Patients.


ABSTRACT: (1) Background: It is known that sickle cells contain a higher amount of Ca2+ compared to healthy red blood cells (RBCs). The increased Ca2+ is associated with the most severe symptom of sickle cell disease (SCD), the vaso-occlusive crisis (VOC). The Ca2+ entry pathway received the name of Psickle but its molecular identity remains only partly resolved. We aimed to map the involved Ca2+ signaling to provide putative pharmacological targets for treatment. (2) Methods: The main technique applied was Ca2+ imaging of RBCs from healthy donors, SCD patients and a number of transgenic mouse models in comparison to wild-type mice. Life-cell Ca2+ imaging was applied to monitor responses to pharmacological targeting of the elements of signaling cascades. Infection as a trigger of VOC was imitated by stimulation of RBCs with lysophosphatidic acid (LPA). These measurements were complemented with biochemical assays. (3) Results: Ca2+ entry into SCD RBCs in response to LPA stimulation exceeded that of healthy donors. LPA receptor 4 levels were increased in SCD RBCs. Their activation was followed by the activation of Gi protein, which in turn triggered opening of TRPC6 and CaV2.1 channels via a protein kinase C? and a MAP kinase pathway, respectively. (4) Conclusions: We found a new Ca2+ signaling cascade that is increased in SCD patients and identified new pharmacological targets that might be promising in addressing the most severe symptom of SCD, the VOC.

SUBMITTER: Wang J 

PROVIDER: S-EPMC7924404 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Lysophosphatidic Acid-Activated Calcium Signaling Is Elevated in Red Cells from Sickle Cell Disease Patients.

Wang Jue J   Hertz Laura L   Ruppenthal Sandra S   El Nemer Wassim W   Connes Philippe P   Goede Jeroen S JS   Bogdanova Anna A   Birnbaumer Lutz L   Kaestner Lars L  

Cells 20210220 2


(1) Background: It is known that sickle cells contain a higher amount of Ca<sup>2+</sup> compared to healthy red blood cells (RBCs). The increased Ca<sup>2+</sup> is associated with the most severe symptom of sickle cell disease (SCD), the vaso-occlusive crisis (VOC). The Ca<sup>2+</sup> entry pathway received the name of P<sub>sickle</sub> but its molecular identity remains only partly resolved. We aimed to map the involved Ca<sup>2+</sup> signaling to provide putative pharmacological targets f  ...[more]

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