Pdz Adaptors: Their Regulation of Epithelial Transporters and Involvement in Human Diseases

Homeostasis in the body is at least partially maintained by mechanisms that control membrane permeability, and thereby serve to control the uptake of essential substances (e.g., nutrients) and the efflux of unwanted substances (e.g., xenobiotics and metabolites) in epithelial cells. Various transporters play fundamental roles in such bidirectional transport, but little is known about how they are organized on plasma membranes. Protein–protein interactions may play a key role: several transporters in epithelial cells interact with the so-called adaptor proteins, which are membrane anchored and interact with both transporters and other membranous proteins. Although most of the evidences for transporter–adaptor interaction has been obtained in vitro, recent studies suggest that adaptor-mediated transporter regulation does occur in vivo and could be relevant to human diseases. Thus, protein–protein interaction is not only associated with the formation of macromolecular complexes but is also involved in various cellular events, and may provide transporters with additional functionality by forming transporter networks on plasma membranes. Interactions between xenobiotic transporters and PSD95/Dlg/ZO1 (PDZ) adaptors were previously reviewed by Kato and Tsuji (2006. Eur J Pharm Sci 27:487–500); the present review focuses on the latest findings about PDZ adaptors as regulators of transporter networks and their potential role in human diseases. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3620–3635, 2011