Activation of protein kinase C by phorbol ester increases red blood cell scramblase activity and external phosphatidylserine

Externalization of phosphatidylserine (PS) is thought to contribute to sickle cell disease (SCD) pathophysiology. The red blood cell (RBC) aminophospholipid translocase (APLT) mediates the transport of PS from the outer to the inner RBC membrane leaflet to maintain an asymmetric distribution of PL,...

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Bibliographic Details
Published in:European journal of haematology 2015-11, Vol.95 (5), p.405-410
Main Authors: Barber, Latorya A., Palascak, Mary B., Qi, Xiaoyang, Joiner, Clinton H., Franco, Robert S.
Format: Article
Language:English
Subjects:
Enzyme Activation - drug effects
Erythrocytes - enzymology
Female
Humans
Male
phorbol ester
phosphatidylserine
Phosphatidylserines - pharmacology
Phospholipid Transfer Proteins - metabolism
protein kinase C
Protein Kinase C - metabolism
red blood cell
scramblase
sickle cell disease
Tetradecanoylphorbol Acetate - pharmacology
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Summary:Externalization of phosphatidylserine (PS) is thought to contribute to sickle cell disease (SCD) pathophysiology. The red blood cell (RBC) aminophospholipid translocase (APLT) mediates the transport of PS from the outer to the inner RBC membrane leaflet to maintain an asymmetric distribution of PL, while phospholipid scramblase (PLSCR) equilibrates PL across the RBC membrane, promoting PS externalization. We previously identified an association between PS externalization level and PLSCR activity in sickle RBC under basal conditions. Other studies showed that activation of protein kinase C (PKC) by PMA (phorbol‐12‐myristate‐13‐acetate) causes increased external PS on RBC. Therefore, we hypothesized that PMA‐activated PKC stimulates PLSCR activity in RBC and thereby contributes to increased PS externalization. In the current studies, we show that PMA treatment causes immediate and variable PLSCR activation and subsequent PS externalization in control and sickle RBC. While TfR+ sickle reticulocytes display some endogenous PLSCR activity, we observed a robust activation of PLSCR in sickle reticulocytes treated with PMA. The PKC inhibitor, chelerythrine (Chel), significantly inhibited PMA‐dependent PLSCR activation and PS externalization. Chel also inhibited endogenous PLSCR activity in sickle reticulocytes. These data provide evidence that PKC mediates PS externalization in RBC through activation of PLSCR.
ISSN:0902-4441
1600-0609
DOI:10.1111/ejh.12506