Decreased expression of multidrug efflux transporters in the brains of GSK-3beta transgenic mice.
Multidrug efflux transporters protect cells in the brain from potentially harmful substances but also from therapeutically useful drugs. Thus any condition that causes changes in their expression is of some importance with regard to drug access. In this study, changes in efflux transporter expression are investigated in mice containing a mutant constitutively active glycogen synthase kinase-3 (GSK-3beta) transgene, driven by the Thy-1 promoter so limiting its localization predominantly to neurons and some glial cells. As expected, decreases in beta-catenin were evident via Western blot analyses of cortical homogenates prepared from brains of these transgenic mice. As assessed by real time qRT-PCR, decreased transcript levels of the mdr1b isoform of P-glycoprotein, Mrp1 and Mrp4, (transporters associated with neurons and/or glial cells) were observed in the cortex but not the subventricular zone or hippocampus of the transgenic compared to wild type mouse brains. By contrast, no such decreases were evident with the mdr1a isoform of P-glycoprotein and Bcrp, transporters predominantly found in brain endothelium. Such transporter expression changes could not be accounted for by alterations in blood vessel density or neuronal to glial cell ratios as analyzed both from immunocytochemical staining and from RT-PCR. These observations support previous in vitro data showing that manipulations to GSK-3beta activity that alter signaling via beta-catenin can influence the expression of efflux transporters. Implications from this are that drug distribution into cells within the brain of these transgenic mice could be enhanced, hence warranting further investigation.
Lim
Joseph C
JC
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
Mickute
Zita
Z
Zaman
Monju
M
Hopkins
Sarah
S
Wijesuriya
Hasini
H
Steckler
Thomas
T
Moechars
Dieder
D
Van Leuven
Fred
F
Sarnyai
Zoltan
Z
Hladky
Stephen B
SB
Barrand
Margery A
MA
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D002452:Cell Count; D004730:Endothelium, Vascular / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051176:beta Catenin / Q000378:metabolism*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012313:RNA; D051176:beta Catenin; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C489540:Abcc4 protein, mouse; C501412:Abcg2 protein, mouse; C495267:CTNNB1 protein, mouse; C000605507:Gsk3b protein, mouse; C421109:multidrug resistance-associated protein 1