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Metabolic remodeling of the human red blood cell membrane.

ABSTRACT: The remarkable deformability of the human red blood cell (RBC) results from the coupled dynamic response of the phospholipid bilayer and the spectrin molecular network. Here we present quantitative connections between spectrin morphology and membrane fluctuations of human RBCs by using dynamic full-field laser interferometry techniques. We present conclusive evidence that the presence of adenosine 5'-triphosphate (ATP) facilitates non-equilibrium dynamic fluctuations in the RBC membrane that are highly correlated with the biconcave shape of RBCs. Spatial analysis of the fluctuations reveals that these non-equilibrium membrane vibrations are enhanced at the scale of spectrin mesh size. Our results indicate that the dynamic remodeling of the coupled membranes powered by ATP results in non-equilibrium membrane fluctuations manifesting from both metabolic and thermal energies and also maintains the biconcave shape of RBCs.

SUBMITTER: Park Y

PROVIDER: S-EPMC2802590 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Metabolic remodeling of the human red blood cell membrane.

Park YongKeun Y Best Catherine A CA Auth Thorsten T Gov Nir S NS Safran Samuel A SA Popescu Gabriel G Suresh Subra S Feld Michael S MS

Proceedings of the National Academy of Sciences of the United States of America 20100106 4

The remarkable deformability of the human red blood cell (RBC) results from the coupled dynamic response of the phospholipid bilayer and the spectrin molecular network. Here we present quantitative connections between spectrin morphology and membrane fluctuations of human RBCs by using dynamic full-field laser interferometry techniques. We present conclusive evidence that the presence of adenosine 5'-triphosphate (ATP) facilitates non-equilibrium dynamic fluctuations in the RBC membrane that are ...[more]

PMID: 20080583

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Project description:UnlabelledBackgroundIn sickle cell disease (SCD), the mitogen-activated protein kinase (MAPK) ERK1/2 is constitutively active and can be inducible by agonist-stimulation only in sickle but not in normal human red blood cells (RBCs). ERK1/2 is involved in activation of ICAM-4-mediated sickle RBC adhesion to the endothelium. However, other effects of the ERK1/2 activation in sickle RBCs leading to the complex SCD pathophysiology, such as alteration of RBC hemorheology are unknown.ResultsTo further characterize global ERK1/2-induced changes in membrane protein phosphorylation within human RBCs, a label-free quantitative phosphoproteomic analysis was applied to sickle and normal RBC membrane ghosts pre-treated with U0126, a specific inhibitor of MEK1/2, the upstream kinase of ERK1/2, in the presence or absence of recombinant active ERK2. Across eight unique treatment groups, 375 phosphopeptides from 155 phosphoproteins were quantified with an average technical coefficient of variation in peak intensity of 19.8%. Sickle RBC treatment with U0126 decreased thirty-six phosphopeptides from twenty-one phosphoproteins involved in regulation of not only RBC shape, flexibility, cell morphology maintenance and adhesion, but also glucose and glutamate transport, cAMP production, degradation of misfolded proteins and receptor ubiquitination. Glycophorin A was the most affected protein in sickle RBCs by this ERK1/2 pathway, which contained 12 unique phosphorylated peptides, suggesting that in addition to its effect on sickle RBC adhesion, increased glycophorin A phosphorylation via the ERK1/2 pathway may also affect glycophorin A interactions with band 3, which could result in decreases in both anion transport by band 3 and band 3 trafficking. The abundance of twelve of the thirty-six phosphopeptides were subsequently increased in normal RBCs co-incubated with recombinant ERK2 and therefore represent specific MEK1/2 phospho-inhibitory targets mediated via ERK2.ConclusionsThese findings expand upon the current model for the involvement of ERK1/2 signaling in RBCs. These findings also identify additional protein targets of this pathway other than the RBC adhesion molecule ICAM-4 and enhance the understanding of the mechanism of small molecule inhibitors of MEK/1/2/ERK1/2, which could be effective in ameliorating RBC hemorheology and adhesion, the hallmarks of SCD.

Dataset Information

Metabolic remodeling of the human red blood cell membrane.

Publications

Metabolic remodeling of the human red blood cell membrane.

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