Regulation of drug transporters by PDZ adaptor proteins and nuclear receptors.
Drug transporters have been suggested to be involved in various aspects of pharmacokinetics. 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.
Kato
Yukio
Y
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan.
Watanabe
Chizuru
C
Tsuji
Akira
A
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D000074011:Peptide Transporter 1; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers; D027981:Symporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C484659:PDZK1 protein, human; D047493:PPAR alpha; D000074011:Peptide Transporter 1; D004364:Pharmaceutical Preparations; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D017923:Sodium-Hydrogen Exchangers; D027981:Symporters; C093376:sodium-hydrogen exchanger regulatory factor