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Review
. 2022 Nov 24;23(23):14667.
doi: 10.3390/ijms232314667.

Regulation of P-Glycoprotein in the Brain

Amanda B Chai  1 , Richard Callaghan  2 , Ingrid C Gelissen  1
Affiliations
Review

Regulation of P-Glycoprotein in the Brain

Amanda B Chai et al. Int J Mol Sci. .

Abstract

Maintenance of the tightly regulated homeostatic environment of the brain is facilitated by the blood-brain barrier (BBB). P-glycoprotein (P-gp), an ATP-binding cassette transporter, is expressed on the luminal surface of the endothelial cells in the BBB, and actively exports a wide variety of substrates to limit exposure of the vulnerable brain environment to waste buildup and neurotoxic compounds. Downregulation of P-gp expression and activity at the BBB have been reported with ageing and in neurodegenerative diseases. Upregulation of P-gp at the BBB contributes to poor therapeutic outcomes due to altered pharmacokinetics of CNS-acting drugs. The regulation of P-gp is highly complex, but unravelling the mechanisms involved may help the development of novel and nuanced strategies to modulate P-gp expression for therapeutic benefit. This review summarises the current understanding of P-gp regulation in the brain, encompassing the transcriptional, post-transcriptional and post-translational mechanisms that have been identified to affect P-gp expression and transport activity.

Keywords: ABCB1; P-glycoprotein; blood–brain barrier; post-transcriptional regulation; post-translational regulation; transcriptional regulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure, location and regulation of P-gp in the brain. The P-gp protein consists of two transmembrane domains, each comprising six membrane-spanning helices, and two intracellular ATP-binding regions (nucleotide-binding domains; NBDs). Phosphorylation sites (serine residues S661, S667, S671 and S683 [6]), depicted by green circles, are located within the linker region connecting the two domains. Glycosylation of P-gp occurs at the asparagine residues N91, N94 and N99 [6], depicted by branched lines between transmembrane helices 1 and 2. In the brain, P-gp is expressed on the luminal surface of BBB endothelial cells. Here, its mRNA and protein expression and activity levels are up- or downregulated by a range of transcription factors, miRNAs and post-translational mechanisms. The expression of P-gp protein has additionally been identified in pericytes, astrocytes [7,8], neurons [7,9] and microglia [10] of the brain.
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This research received no external funding.