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Publications

Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Epublish 16 citations

PubMed: 33672679 DOI: 10.3390/cells10020456

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

Cells 10(2)

Authors: Jue Wang, Laura Hertz, Sandra Ruppenthal, Wassim El Nemer, Philippe Connes, Jeroen S Goede, Anna Bogdanova, Lutz Birnbaumer, Lars Kaestner

Affiliations

  • Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.
  • Theoretical Medicine and Biosciences, Saarland University, 66421 Homburg, Germany.
  • Experimental Physics, Dynamics of Fluids, Saarland University, 66123 Saarbrücken, Germany.
  • Gynaecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, 66421 Homburg, Germany.
  • Etablissement Français du Sang PACA-Corse, Aix Marseille Université, EFS, CNRS, ADES, 13005 Marseille, France.
  • Laboratoire d'Excellence GR-Ex, 75015 Paris, France.
  • Laboratory LIBM EA7424, Vascular Biology and Red Blood Cell Teal, University Claude Bernard Lyon 1, 69008 Lyon, France.
  • Division of Oncology and Hematology, Kantonsspital Winterthur, CH-8401 Winterthur, Switzerland.
  • Red Blood Cell Research Group, Institute of Veterinary Physiology, University of Zürich, CH-8057 Zürich, Switzerland.
  • Institute of Biomedical Research (BIOMED), Catholic University of Argentina, C1107AFF Buenos Aires, Argentina.
  • Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.

Abstract

(1) Background: It is known that sickle cells contain a higher amount of Ca compared to healthy red blood cells (RBCs). The increased Ca is associated with the most severe symptom of sickle cell disease (SCD), the vaso-occlusive crisis (VOC). The Ca entry pathway received the name of P but its molecular identity remains only partly resolved. We aimed to map the involved Ca signaling to provide putative pharmacological targets for treatment. (2) Methods: The main technique applied was Ca imaging of RBCs from healthy donors, SCD patients and a number of transgenic mouse models in comparison to wild-type mice. Life-cell Ca 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: Ca 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 G protein, which in turn triggered opening of TRPC6 and Ca2.1 channels via a protein kinase Cα and a MAP kinase pathway, respectively. (4) Conclusions: We found a new Ca 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.

MeSH

Cells, Erythrocytes, Anemia, Sickle Cell, Calcium, Calcium Signaling

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