Regulation of drug transporters by PDZ adaptor proteins and nuclear receptors

Abstract

Drug transporters have been suggested to be involved in various aspects of pharmacokinetics, including absorption, distribution and excretion. Identification and characterization of drug transporters have given us a scientific basis for understanding drug disposition, as well as the molecular mechanisms of drug interaction and inter-individual/inter-species differences. On the other hand, regulatory mechanisms of drug transporters are still poorly understood, and information is limited to induction and down-regulation of drug transporters by various microsomal enzyme inducers. Little is known about the molecular machinery that directly interacts with the drug transporters. As a first step to clarify such molecular mechanisms, recent studies have identified PDZ (PSD-95/Discs-large/ZO-1) domain-containing proteins that directly interact with the so-called PDZ binding motif located at the C-terminus of drug transporters.Some of the PDZ proteins have been suggested to regulate transporters via at least two pathways, i.e., stabilization at the cell-surface and direct modulation of transporter function. Therefore, it is possible that membrane transport of therapeutic agents is not only governed by the drug transporters themselves, but also indirectly by PDZ proteins. The PDZ proteins are classified as a family, the members of which are thought to have distinct, but also redundant physiological roles. The purpose of this review article is to summarize the available knowledge on protein interactions and functional modulation of drug transporters.-3 - Overview 1-1) IntroductionRecent progress in molecular biology has led to the identification of various types of drug transporters which accept therapeutic agents as substrates. Drug transporters are generally classified into the SLC (solute carrier) and ABC (ATP-binding cassette) superfamilies. These drug transporters are believed to be directly involved in various aspects of drug disposition, such as absorption, distribution and excretion of drugs (Sai and Tsuji 2004; Shitara et al., 2004;Marzolini et al., 2004;Hagenbuch and Meier 2003;Jonker and Schinkel 2004). However, little is yet known about how these transporters are organized in the plasma membranes, and how their expression and function are regulated. Protein-protein interaction is involved in many biological events, including signal transduction, intracellular trafficking, scaffold formation for protein networks, cellular polarization and protein turnover. In this review article, therefore, we summarize recent findings on direct interaction of drug transporters with so-called adaptor proteins that contain PDZ (PSD-95/Discs-large/ZO-1)

Transcriptional regulation of urate transportosome member SLC2A9 by nuclear receptor HNF4α

“…In addition, SNPs in the PDZ domain containingprotein 1 (PDZK1) gene have been reported to be associated with urate homeostasis. This membrane-associated scaffold protein contains several PDZ domains, which interact with specific C-terminal PDZ-binding motifs of other proteins, thereby coordinating membrane localization, signal transduction, and posttranslational modifications of its targets (21). Functional interaction of PDZK1 has been shown for uptake transporters URAT1 and OAT4 as well as for efflux transporters NPT1 and ABCG2, thereby suggesting that PDZK1 stabilizes the apical urate transporter network (1,10,27,40).…”

Testing Whether MRP4 (a cAMP Efflux Pump) and the Beta 2 Andrenergic Receptor (an Upstream Regulator of cAMP Signaling Pathways

“…This complex formation may result in physical and/or functional interaction of proteins. This interaction may even aid in cell surface expression of the interacting proteins and may also affect different signal transduction pathways in which these interacting proteins are involved [27]. Our interest is in interactions between transporters and their interacting partners, like ion channels, receptors and other transporters, etc.…”

“…This mechanism may act as a regulator for expression of transcripts of MRP4 in a particular cellular environment, which subsequently may control the expression of functional MRP4 protein [7]. While MRP4 is ubiquitously expressed, localization of MRP4 is unique when compared to more restricted cellular/tissue localization of MRP2 or CFTR [8,9]. In addition, while MRP2 and CFTR are apically expressed, MRP4 in some tissues is apically localized and in other tissues is basally localized [5].…”

“…Some of the transporters either in SLC or ABC come under the class I PDZ motifs. Proteins with class I PDZ motifs include MRP2, CFTR, MRP4, OAT4, OCTN1, OCTN2 and Β2AR [26,27,38]. Class II PDZ motifs have the following pattern of amino acids at their carboxy terminal "X-Φ/ -X-Φ/," which is any amino acid at -3 position, hydrophobic or aromatic amino acid at -2 position, any amino acid at -1 position and hydrophobic/ aromatic amino acid 0 position.…”

“…Complex scaffolding proteins are those proteins that have other protein interaction domains along with PDZ domains, e.g., NHERF1, MAGI3 and MUPP1, etc. [27]. Family-based proteins are classified based on a family.…”