Regulation of P-Glycoprotein in the Brain

• Published in: International journal of molecular sciences 2022-11, Vol.23 (23), p.14667
• Main Authors: Chai, Amanda B, Callaghan, Richard, Gelissen, Ingrid C
• Format: Article
• Language: English
• Subjects: Aging; Alzheimer's disease; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain - metabolism; Central Nervous System Agents; Convulsions & seizures; Drug resistance; Endothelial cells; Endothelial Cells - metabolism; Glycoproteins; Kinases; Ligands; Neurotoxicity; Oxidative stress; P-Glycoprotein; Peptides; Pharmacokinetics; Post-transcription; Post-translation; Protein expression; Proteins; Review; Transcription factors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232314667

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.