2. Academic Validation
  3. Pb(II) Induces Scramblase Activation and Ceramide-Domain Generation in Red Blood Cells

Pb(II) Induces Scramblase Activation and Ceramide-Domain Generation in Red Blood Cells

  • Sci Rep. 2018 May 10;8(1):7456. doi: 10.1038/s41598-018-25905-8.
Hasna Ahyayauch 1 2 3,  Aritz B García-Arribas 1 4,  Jesús Sot 1,  Emilio J González-Ramírez 1 4,  Jon V Busto 1 4,  Bingen G Monasterio 1 4,  Noemi Jiménez-Rojo 1 4 5,  F Xabier Contreras 1 4,  Adela Rendón-Ramírez 1 4,  Cesar Martin 1 4,  Alicia Alonso 1 4,  Félix M Goñi 6 7
Affiliations

Affiliations

  • 1 Instituto Biofisika (CSIC, UPV/EHU), 48080, Bilbao, Spain.
  • 2 Institut Supérieur des Professions Infirmières et des Techniques de Santé, Rabat, Morocco.
  • 3 Neuroendocrinology Unit, Laboratory of Genetics, Neuroendocrinology and Biotechnology, Faculty of Sciences, Ibn Tofail University, Kenitra, Morocco.
  • 4 Departamento de Bioquímica, University of the Basque Country (UPV/EHU), 48080, Bilbao, Spain.
  • 5 NCCR Chemical Biology, Department of Biochemistry, University of Geneva, 1211, Geneva, Switzerland.
  • 6 Instituto Biofisika (CSIC, UPV/EHU), 48080, Bilbao, Spain. felix.goni@ehu.eus.
  • 7 Departamento de Bioquímica, University of the Basque Country (UPV/EHU), 48080, Bilbao, Spain. felix.goni@ehu.eus.
PMID: 29748552 DOI: 10.1038/s41598-018-25905-8
Abstract

The mechanisms of Pb(II) toxicity have been studied in human red blood cells using confocal microscopy, immunolabeling, fluorescence-activated cell sorting and atomic force microscopy. The process follows a sequence of events, starting with calcium entry, followed by potassium release, morphological change, generation of ceramide, lipid flip-flop and finally Cell Lysis. Clotrimazole blocks potassium channels and the whole process is inhibited. Immunolabeling reveals the generation of ceramide-enriched domains linked to a cell morphological change, while the use of a neutral sphingomyelinase inhibitor greatly delays the process after the morphological change, and lipid flip-flop is significantly reduced. These facts point to three major checkpoints in the process: first the upstream exchange of calcium and potassium, then ceramide domain formation, and finally the downstream scramblase activation necessary for Cell Lysis. In addition, partial non-cytotoxic Cholesterol depletion of red blood cells accelerates the process as the morphological change occurs faster. Cholesterol could have a role in modulating the properties of the ceramide-enriched domains. This work is relevant in the context of cell death, heavy metal toxicity and sphingolipid signaling.

Figures