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

Abstract

Homeostasis in the body is at least partially maintained by mechanisms that

Sorting Nexin 27 Interacts with Multidrug Resistance-associated Protein 4 (MRP4) and Mediates Internalization of MRP4

“…MRP4 comprises 12 putative membrane-spanning domains and two ATP-binding motifs and contains a consensus class I PDZ-binding motif (PDZ-bm) at the C-terminal end (ETAL; X(S/T)X, where X represents an unspecified residue and is a hydrophobic residue) (1,8). The PDZ-bm interacts with pro-teins containing a PDZ domain through a protein-protein interaction module, which is called PDZ-PDZ interaction, and mediates the correct sorting and tethering of membrane proteins to a specific subcellular localization by assembling the protein complex through this interaction (8,9).…”

“…The PDZ-bm interacts with pro-teins containing a PDZ domain through a protein-protein interaction module, which is called PDZ-PDZ interaction, and mediates the correct sorting and tethering of membrane proteins to a specific subcellular localization by assembling the protein complex through this interaction (8,9). It is conceivable that some PDZ domain-containing proteins interact with MRP4 via PDZ-PDZ interaction and modulate its expression on the plasma membrane.…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…NHERF proteins alter drug transporter function in vitro, as well as drug absorption and disposition in vivo (Park et al, 2014). NHERF proteins are highly expressed at apical membranes of polarized epithelial cells of the kidney, intestine, and liver, where they interact with numerous drug transporters from both SLC and ABC superfamilies (Kato et al, 2004Sugiura et al, 2011). The majority of reported interactions are mediated through canonical class I PDZ ligands, although interactions with drug transporters possessing class II and III PDZ ligands also have been described (Kato et al, 2004;Sugiura et al, 2008;Shimizu et al, 2011).…”

“…Hence, NHERF proteins may have an indirect effect on drug response attributable to their influence on drug absorption and disposition in these important pharmacological barriers. Over the last decade, PDZ proteins have gained considerable attention as post-translational regulators of drug transporter function (Miyazaki et al, 2005;Kato et al, 2006;Noshiro et al, 2006;Sugiura et al, 2006Sugiura et al, , 2008Sugiura et al, , 2010Sugiura et al, , 2011Choi et al, 2011;Park et al, 2014;Wang et al, 2014;Zheng et al, 2014). To highlight these new findings, we review the current knowledge of drug transporter regulation by PDZ proteins and address the association of PDZ proteins with drug disposition and response in select disease states.…”

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

“…Transporters having PDZ motifs are mostly anchored to the apical membranes in polarized cells. PDZ motifs may play a role in the sorting of transporters to the membrane along with other signals that are required for membrane anchoring [27,50,51]. Membrane sorting of transporters like MRP2, CFTR and MRP4 in some cell types is based on the interaction between the PDZ motif and PDZ domains of scaffolding proteins [27,47,51,52].…”