The Impact of Ca2+ on Intracellular Distribution of Hemoglobin in Human Erythrocytes

Leonid Livshits*, Sari Peretz, Anna Bogdanova, Hiba Zoabi, Harel Eitam, Gregory Barshtein, Cindy Galindo, Yuri Feldman, Ivana Pajić-Lijaković, Ariel Koren, Max Gassmann, Carina Levin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The membrane-bound hemoglobin (Hb) fraction impacts red blood cell (RBC) rheology and metabolism. Therefore, Hb–RBC membrane interactions are precisely controlled. For instance, the signaling function of membrane-bound deoxy-Hb and the structure of the docking sites in the cytosolic domain of the anion exchanger 1 (AE-1) protein are well documented; however, much less is known about the interaction of Hb variants with the erythrocyte’s membrane. Here, we identified factors other than O2 availability that control Hb abundance in the membrane-bound fraction and the possible variant-specific binding selectivity of Hb to the membrane. We show that depletion of extracellular Ca2+ by chelators, or its omission from the extracellular medium, leads to membrane-bound Hb release into the cytosol. The removal of extracellular Ca2+ further triggers the redistribution of HbA0 and HbA2 variants between the membrane and the cytosol in favor of membrane-bound HbA2. Both effects are reversible and are no longer observed upon reintroduction of Ca2+ into the extracellular medium. Fluctuations of cytosolic Ca2+ also impact the pre-membrane Hb pool, resulting in the massive transfer of Hb to the cellular cytosol. We hypothesize that AE-1 is the specific membrane target and discuss the physiological outcomes and possible clinical implications of the Ca2+ regulation of the intracellular Hb distribution.

Original languageAmerican English
Article number2280
Issue number18
StatePublished - 15 Sep 2023

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  • calcium
  • hemoglobin A2
  • hemoglobin distribution
  • red blood cells


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