{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:33:09Z","timestamp":1768455189874,"version":"3.49.0"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,4,24]],"date-time":"2015-04-24T00:00:00Z","timestamp":1429833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL070871"],"award-info":[{"award-number":["HL070871"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["European J of Haematology"],"published-print":{"date-parts":[[2015,11]]},"abstract":"Abstract<\/jats:title>Externalization of phosphatidylserine (PS<\/jats:styled-content>) is thought to contribute to sickle cell disease (SCD<\/jats:styled-content>) pathophysiology. The red blood cell (RBC<\/jats:styled-content>) aminophospholipid translocase (APLT<\/jats:styled-content>) mediates the transport of PS<\/jats:styled-content> from the outer to the inner RBC<\/jats:styled-content> membrane leaflet to maintain an asymmetric distribution of PL<\/jats:styled-content>, while phospholipid scramblase (PLSCR<\/jats:styled-content>) equilibrates PL<\/jats:styled-content> across the RBC<\/jats:styled-content> membrane, promoting PS<\/jats:styled-content> externalization. We previously identified an association between PS<\/jats:styled-content> externalization level and PLSCR<\/jats:styled-content> activity in sickle RBC<\/jats:styled-content> under basal conditions. Other studies showed that activation of protein kinase C (PKC<\/jats:styled-content>) by PMA<\/jats:styled-content> (phorbol\u201012\u2010myristate\u201013\u2010acetate) causes increased external PS<\/jats:styled-content> on RBC<\/jats:styled-content>. Therefore, we hypothesized that PMA<\/jats:styled-content>\u2010activated PKC<\/jats:styled-content> stimulates PLSCR<\/jats:styled-content> activity in RBC<\/jats:styled-content> and thereby contributes to increased PS<\/jats:styled-content> externalization. In the current studies, we show that PMA<\/jats:styled-content> treatment causes immediate and variable PLSCR<\/jats:styled-content> activation and subsequent PS<\/jats:styled-content> externalization in control and sickle RBC<\/jats:styled-content>. While TfR+ sickle reticulocytes display some endogenous PLSCR<\/jats:styled-content> activity, we observed a robust activation of PLSCR<\/jats:styled-content> in sickle reticulocytes treated with PMA<\/jats:styled-content>. The PKC<\/jats:styled-content> inhibitor, chelerythrine (Chel), significantly inhibited PMA<\/jats:styled-content>\u2010dependent PLSCR<\/jats:styled-content> activation and PS<\/jats:styled-content> externalization. Chel also inhibited endogenous PLSCR<\/jats:styled-content> activity in sickle reticulocytes. These data provide evidence that PKC<\/jats:styled-content> mediates PS<\/jats:styled-content> externalization in RBC<\/jats:styled-content> through activation of PLSCR<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/ejh.12506","type":"journal-article","created":{"date-parts":[[2015,1,20]],"date-time":"2015-01-20T10:26:31Z","timestamp":1421749591000},"page":"405-410","source":"Crossref","is-referenced-by-count":4,"title":["Activation of protein kinase C by phorbol ester increases red blood cell scramblase activity and external phosphatidylserine"],"prefix":"10.1111","volume":"95","author":[{"given":"Latorya A.","family":"Barber","sequence":"first","affiliation":[{"name":"Division of Internal Medicine\u2010Hematology\/Oncology University of Cincinnati College of Medicine Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary B.","family":"Palascak","sequence":"additional","affiliation":[{"name":"Division of Internal Medicine\u2010Hematology\/Oncology University of Cincinnati College of Medicine Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyang","family":"Qi","sequence":"additional","affiliation":[{"name":"Division of Internal Medicine\u2010Hematology\/Oncology University of Cincinnati College of Medicine Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clinton H.","family":"Joiner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Hematology Oncology Children's Healthcare of Atlanta Aflac Cancer and Blood Disorders Center Emory University Atlanta GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert S.","family":"Franco","sequence":"additional","affiliation":[{"name":"Division of Internal Medicine\u2010Hematology\/Oncology University of Cincinnati College of Medicine Cincinnati OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,4,24]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/00062752-199803000-00007"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-005-5099-y"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.12.6603"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.29.18240"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2009.07760.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(87)90376-2"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1054\/ceca.1999.0029"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.3.860"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-04-1630"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1997.273.4.C1206"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002770100352"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2960675"},{"key":"e_1_2_7_14_1","doi-asserted-by":"crossref","first-page":"7701","DOI":"10.1016\/S0021-9258(19)57457-9","article-title":"Phorbol ester\u2010 and Ca2+\u2010dependent phosphorylation of human red cell membrane skeletal proteins","volume":"261","author":"Cohen CM","year":"1986","journal-title":"J Biol Chem"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410650200"},{"key":"e_1_2_7_16_1","doi-asserted-by":"crossref","first-page":"16021","DOI":"10.1016\/S0021-9258(17)36360-3","article-title":"Protein kinase C in the human erythrocyte. 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