title: P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery.
abstract: The primary function of the blood-brain barrier (BBB)/neurovascular unit is to protect the central nervous system (CNS) from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter, we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain-induced changes in P-gp trafficking are associated with changes in P-gp's association with caveolin-1, a key scaffolding/trafficking protein that colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization, and activation of P-gp "pools" between microvascular endothelial cell subcellular compartments. Since redox-sensitive processes may be involved in signaling disassembly of higher-order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface, providing improved CNS drug delivery. The advantage of therapeutic drug "relocalization" of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA. Electronic address: davistp@email.arizona.edu.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Sanchez-Covarubias
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Tome
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D021381:Protein Transport
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations
keywords: ATP-binding cassette transporter; Blood–brain barrier; Drug delivery; Neurovascular unit; P-glycoprotein; Peripheral inflammatory pain; Protein trafficking; Reactive oxygen species; Redox-sensitive protein pools