Fig. 4

Summary of signaling pathways. Signaling pathways that regulate a P-gp, b BCRP, and c Mrp2 at the blood–brain barrier. Clockwise: ET-1 signaling upregulates P-gp, but downregulates BCRP and Mrp2. The nuclear receptor pregane X receptor (PXR) upregulates P-gp and Mrp2, the farnesoid X receptor (FXR) upregulates Mrp2, and the constitutive androstane receptor (CAR) upregulates P-gp, BCRP, and Mrp2. Estradiol (E2) signals through the estrogen receptor β (ERβ) to stimulate proteasomal degradation of P-gp and BCRP. Amyloid-β (Aβ) triggers degradation of P-gp but has no effect on BCRP. Glutamate released during seizures signals through the N-methyl-d-aspartate receptor (NMDAR) and cyclooxygenase-2 (COX-2) upregulation of P-gp, BCRP, and Mrp2. Diesel exhaust particles (DEP) activate NADPH oxidase resulting in P-gp, BCRP, and Mrp2 induction. TNF-α signaling through TNF-R1 upregulates P-gp and downregulates Mrp2, but has no effect on BCRP