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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.


Mol Pharm. 2012 Sep 21;


Authors: Harati R, Benech H, Villegier AS, Mabondzo A


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-gp, BCRP, oat3, 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 rats brain, 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 co-culture 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.

PMID: 22998451 [PubMed - as supplied by publisher]