title: P-glycoprotein, breast cancer resistance protein, Organic Anion Transporter 3, and Transporting Peptide 1a4 during blood-brain barrier maturation: involvement of Wnt/β-catenin and endothelin-1 signaling.
abstract: Our current knowledge about drug transporters in the maturational brain is very limited. In this study, we provide a comprehensive overview of the expression and activity profile of P-glycoprotein (P-gp), Breast Cancer Resistance Protein (bcrp), Organic Anion Transporter 3 (oat3), and Transporting Peptide 1a4 (oatp1a4) transporters during blood-brain barrier (BBB) maturation. Gene and protein expressions of the analyzed transporters increase as the brain matures, with no variation in their activity for P-gp and bcrp, while the transport activity of oat3 and oatp1a4 increases during brain maturation from preterm up to adulthood. For the first time, we illustrate a downregulation of nuclear β-catenin expression in brain capillaries when bcrp, P-gp, oat3, and oatp1a4 transporters are at their highest expression levels. In vivo activation of β-catenin in rat brains, by intracerebroventricular (ICV) injection of a GSK-3 inhibitor, enhances the activity of P-gp, bcrp, oat3, and oatp1a4. Interestingly, in an in vitro BBB model consisting of a coculture of primary endothelial brain cells with astrocytes or in vivo, activation of β-catenin enhances the mRNA expression of ET-1. Interestingly, blocking the ETA receptor for endothelin-1 in vivo by ICV injection of a ETA antagonist decreases transporter activity mediated by the activation of β-catenin. These findings shed light on the role of an interaction between β-catenin and endothelin-1 signaling in the regulation of these transporters at the BBB.
authors.affiliation: CEA, Direction des Sciences du Vivant, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, 91191 Gif-sur-Yvette, France.
authors.forename: Rania
authors.initials: R
authors.lastname: Harati
authors.forename: Henri
authors.initials: H
authors.lastname: Benech
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Villégier
authors.forename: Aloïse
authors.initials: A
authors.lastname: Mabondzo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008959:Models, Neurological; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C503597:Slco1a4 protein, rat; D051176:beta Catenin; C114338:organic anion transport protein 3; D038362:Glycogen Synthase Kinase 3