title: Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity.
abstract: Erythrocyte possesses high sphingosine kinase 1 (SphK1) activity and is the major cell type supplying plasma sphingosine-1-phosphate, a signaling lipid regulating multiple physiological and pathological functions. Recent studies revealed that erythrocyte SphK1 activity is upregulated in sickle cell disease (SCD) and contributes to sickling and disease progression. However, how erythrocyte SphK1 activity is regulated remains unknown. Here we report that adenosine induces SphK1 activity in human and mouse sickle and normal erythrocytes in vitro. Next, using 4 adenosine receptor-deficient mice and pharmacological approaches, we determined that the A2B adenosine receptor (ADORA2B) is essential for adenosine-induced SphK1 activity in human and mouse normal and sickle erythrocytes in vitro. Subsequently, we provide in vivo genetic evidence that adenosine deaminase (ADA) deficiency leads to excess plasma adenosine and elevated erythrocyte SphK1 activity. Lowering adenosine by ADA enzyme therapy or genetic deletion of ADORA2B significantly reduced excess adenosine-induced erythrocyte SphK1 activity in ADA-deficient mice. Finally, we revealed that protein kinase A-mediated extracellular signal-regulated kinase 1/2 activation functioning downstream of ADORA2B underlies adenosine-induced erythrocyte SphK1 activity. Overall, our findings reveal a novel signaling network regulating erythrocyte SphK1 and highlight innovative mechanisms regulating SphK1 activity in normal and SCD.
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Science, and.
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Bogdanov
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Anren
authors.initials: A
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Jessica
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: William
authors.initials: W
authors.lastname: Dowhan
authors.affiliation: Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX.
authors.forename: Modupe
authors.initials: M
authors.lastname: Idowu
authors.affiliation: Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX.
authors.forename: Harinder S
authors.initials: HS
authors.lastname: Juneja
authors.affiliation: Department of Biochemistry and Molecular Biology.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Molina
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Science, and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Science, and.
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Science, and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000241:Adenosine / Q000097:blood*; D000243:Adenosine Deaminase / Q000097:blood / Q000172:deficiency / Q000235:genetics; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000361:Agammaglobulinemia / Q000097:blood / Q000201:enzymology / Q000235:genetics; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004913:Erythrocytes, Abnormal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006451:Hemoglobin, Sickle / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000097:blood*; D043704:Receptor, Adenosine A2B / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000097:blood / Q000201:enzymology / Q000235:genetics; D015398:Signal Transduction; D000099157:Sphingosine Kinase
chemical_list: D000241:Adenosine; D000243:Adenosine Deaminase; D019830:Adenosine-5'-(N-ethylcarboxamide); D017868:Cyclic AMP-Dependent Protein Kinases; D006451:Hemoglobin, Sickle; D017853:Phosphotransferases (Alcohol Group Acceptor); D043704:Receptor, Adenosine A2B; D000099157:Sphingosine Kinase