Dataset Information

Epinephrine modulates BCAM/Lu and ICAM-4 expression on the sickle cell trait red blood cell membrane.

ABSTRACT: Collapse and sudden death in physical training are the most serious complications of sickle cell trait (SCT). There is evidence that erythrocytes in SCT patients aggregate during strenuous exercise, likely because of adhesive interactions with the extracellular matrix (ECM) and endothelial cells, and because of their irregular viscoelastic properties. This results in inflammation, blood flow impairment, and vaso-occlusive events. However, the exact role of stress conditions and how they lead to these complications is virtually unknown. Using single-molecule atomic force microscopy experiments, we found that epinephrine, a hormone that is secreted under stressful conditions, increases both the frequency and strength of adhesion events between basal cell adhesion molecule (BCAM/Lu) and ECM laminin, and between intercellular adhesion molecule-4 (ICAM-4) and endothelial ?(v)?(3), compared with nonstimulated SCT erythrocytes. Increases in adhesion frequency provide significant evidence of the role of epinephrine in BCAM/Lu-laminin and ICAM-4-?(v)?(3) bonding, and suggest mechanisms of vaso-occlusion during physical exertion in SCT.

SUBMITTER: Maciaszek JL

PROVIDER: S-EPMC3296041 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Epinephrine modulates BCAM/Lu and ICAM-4 expression on the sickle cell trait red blood cell membrane.

Maciaszek Jamie L JL Andemariam Biree B Huber Greg G Lykotrafitis George G

Biophysical journal 20120306 5

Collapse and sudden death in physical training are the most serious complications of sickle cell trait (SCT). There is evidence that erythrocytes in SCT patients aggregate during strenuous exercise, likely because of adhesive interactions with the extracellular matrix (ECM) and endothelial cells, and because of their irregular viscoelastic properties. This results in inflammation, blood flow impairment, and vaso-occlusive events. However, the exact role of stress conditions and how they lead to ...[more]

PMID: 22404936

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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

Epinephrine modulates BCAM/Lu and ICAM-4 expression on the sickle cell trait red blood cell membrane.

Publications

Epinephrine modulates BCAM/Lu and ICAM-4 expression on the sickle cell trait red blood cell membrane.

Similar Datasets

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