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.
| Main Authors: | , , , , , , , , |
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| Format: | Artículo biblioteca |
| Language: | eng |
| Published: |
MDPI
2021
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| Subjects: | ENFERMEDAD DE CELULAS FALCIFORMES, ERITROCITOS, HISTOLOGIA, CALCIO, ANEMIA HEMOLITICA, |
| Online Access: | https://repositorio.uca.edu.ar/handle/123456789/11619 https://doi.org/10.3390/cells10020456 |
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| Summary: | 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. |
|---|