{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T07:54:51Z","timestamp":1777622091617,"version":"3.51.4"},"reference-count":87,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T00:00:00Z","timestamp":1613779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["860436"],"award-info":[{"award-number":["860436"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Z01-ES101643"],"award-info":[{"award-number":["Z01-ES101643"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>(1) Background: It is known that sickle cells contain a higher amount of Ca2+ compared to healthy red blood cells (RBCs). The increased Ca2+ is associated with the most severe symptom of sickle cell disease (SCD), the vaso-occlusive crisis (VOC). The Ca2+ entry pathway received the name of Psickle but its molecular identity remains only partly resolved. We aimed to map the involved Ca2+ signaling to provide putative pharmacological targets for treatment. (2) Methods: The main technique applied was Ca2+ imaging of RBCs from healthy donors, SCD patients and a number of transgenic mouse models in comparison to wild-type mice. Life-cell Ca2+ imaging was applied to monitor responses to pharmacological targeting of the elements of signaling cascades. Infection as a trigger of VOC was imitated by stimulation of RBCs with lysophosphatidic acid (LPA). These measurements were complemented with biochemical assays. (3) Results: Ca2+ entry into SCD RBCs in response to LPA stimulation exceeded that of healthy donors. LPA receptor 4 levels were increased in SCD RBCs. Their activation was followed by the activation of Gi protein, which in turn triggered opening of TRPC6 and CaV2.1 channels via a protein kinase C\u03b1 and a MAP kinase pathway, respectively. (4) Conclusions: We found a new Ca2+ signaling cascade that is increased in SCD patients and identified new pharmacological targets that might be promising in addressing the most severe symptom of SCD, the VOC.<\/jats:p>","DOI":"10.3390\/cells10020456","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T13:17:02Z","timestamp":1613827022000},"page":"456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Lysophosphatidic Acid-Activated Calcium Signaling Is Elevated in Red Cells from Sickle Cell Disease Patients"],"prefix":"10.3390","volume":"10","author":[{"given":"Jue","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Hertz","sequence":"additional","affiliation":[{"name":"Theoretical Medicine and Biosciences, Saarland University, 66421 Homburg, Germany"},{"name":"Experimental Physics, Dynamics of Fluids, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Ruppenthal","sequence":"additional","affiliation":[{"name":"Experimental Physics, Dynamics of Fluids, Saarland University, 66123 Saarbr\u00fccken, Germany"},{"name":"Gynaecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, 66421 Homburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8184-427X","authenticated-orcid":false,"given":"Wassim","family":"El Nemer","sequence":"additional","affiliation":[{"name":"Etablissement Fran\u00e7ais du Sang PACA-Corse, Aix Marseille Universit\u00e9, EFS, CNRS, ADES, 13005 Marseille, France"},{"name":"Laboratoire d\u2019Excellence GR-Ex, 75015 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9232-0268","authenticated-orcid":false,"given":"Philippe","family":"Connes","sequence":"additional","affiliation":[{"name":"Laboratoire d\u2019Excellence GR-Ex, 75015 Paris, France"},{"name":"Laboratory LIBM EA7424, Vascular Biology and Red Blood Cell Teal, University Claude Bernard Lyon 1, 69008 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeroen S.","family":"Goede","sequence":"additional","affiliation":[{"name":"Division of Oncology and Hematology, Kantonsspital Winterthur, CH-8401 Winterthur, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0502-5381","authenticated-orcid":false,"given":"Anna","family":"Bogdanova","sequence":"additional","affiliation":[{"name":"Red Blood Cell Research Group, Institute of Veterinary Physiology, University of Z\u00fcrich, CH-8057 Z\u00fcrich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lutz","family":"Birnbaumer","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Research (BIOMED), Catholic University of Argentina, C1107AFF Buenos Aires, Argentina"},{"name":"Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Kaestner","sequence":"additional","affiliation":[{"name":"Theoretical Medicine and Biosciences, Saarland University, 66421 Homburg, Germany"},{"name":"Experimental Physics, Dynamics of Fluids, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/298478a0","article-title":"Physiological [Ca2+]i Level and Pump-Leak Turnover in Intact Red Cells Measured Using an Incorporated Ca Chelator","volume":"298","author":"Lew","year":"1982","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1172\/JCI116857","article-title":"Effects of Deoxygenation on Active and Passive Ca2+ Transport and on the Cytoplasmic Ca2+ Levels of Sickle Cell Anemia Red Cells","volume":"92","author":"Etzion","year":"1993","journal-title":"J. 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