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
Rania Harati
Henri Benech
Anne Sophie Villégier
Aloïse Mabondzo
10.1021/mp300334r.s001
https://acs.figshare.com/articles/journal_contribution/P_Glycoprotein_Breast_Cancer_Resistance_Protein_Organic_Anion_Transporter_3_and_Transporting_Peptide_1a4_during_Blood_Brain_Barrier_Maturation_Involvement_of_Wnt_Catenin_and_Endothelin_1_Signaling/2418397
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. <i>In vivo</i> 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 <i>in vitro</i> BBB model consisting of a coculture of primary endothelial brain
cells with astrocytes or <i>in vivo</i>, activation of β-catenin
enhances the mRNA expression of ET-1. Interestingly, blocking the
ETA receptor for endothelin-1 <i>in vivo</i> 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.
2016-02-19 10:03:37
oatp 1a increases
GSK
activation
Peptide 1
oatp 1a transporters
expression
bcrp
BBB
vivo
catenin
ICV
ETA antagonist decreases transporter activity