REGULATION OF DRUG TRANSPORTER ACTIVITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 526

order to fulfill the transport missions assigned to each of the many different epithelial
cell types. The actual destination to which a given transporter is directed is chosen by
the epithelial cell and is determined through protein-protein interactions between the
transporter and the components of the sorting machinery expressed by the epithelial
cells. In this manner, each type of transporting epithelial cell can differentially dis-
tribute transport proteins so as to achieve the localizations required by its particular
physiological role. Abnormal membrane sorting and trafficking of the transporters
is the key cause for many clinical syndromes. 36 − 38 After the sorting machinery deliv-
ers the transporter to a specific cell surface, maintenance of the correct localization at
that surface requires interactions of the transporters with structural proteins located at
or near the plasma membrane. It has been shown that the protein-protein interactions
that orchestrate the polarized distributions of transport proteins may also regulate their
functions. Certain transport proteins are not constitutive components of a particular
cell surface domain. Instead, these proteins commute or recycle between the cell sur-
face and an intracellular storage compartment. In response to concentration changes
in intracellular second messenger(s) concentrations, transporters are either inserted
into or retrieved from the cell surface. By manipulating the surface populations of se-
lected transport proteins, epithelial cells can precisely modulate their physiologic(al)
properties. Therefore, during their journey from the endoplasmic reticulum through
the secretary pathway to the cell surface, transporters interact with various accessory
proteins. It is these interactions that determine their localization on the specific cell
surface, domain, their stability at the specific cell surface, and their shuttling be-
tween the specific cell surface and the intracellular compartments when responding
to stimuli.
Many drug transporters have been shown to be associated with other proteins to
fulfill their function(s). PDZ proteins, for example, are one of the most common
interacting partners with transporters. PDZ proteins contain multiple PDZ domains
ranging from 80 to 90 amino acids in length and bind typically to proteins containing
PDZ consensus binding sites, the tripeptide motif (S/T)X (X =

a hydrophobic residue) at their C-termini. 39 These multidomain molecules not only
target and provide scaffolds for protein-protein interactions but also modulate the
function of receptors and ion channels by which they associate. 40 , 41 The disruption of
the association between PDZ proteins and their targets contributes to the pathogenesis
of a number of human diseases, probably because of the failure of PDZ proteins to
appropriately target and modulate the actions of associated proteins. 42 , 43
Several known members of the organic anion transporter polypeptide (OATP)
family have PDZ consensus-binding sites. Studies using protein mass fingerprinting
and immunoprecipitation 44 showed that PDZ protein PDZK1 is the major interacting
protein of Oatp1a1 both in 293T cells cotransfected with Oatp1a1 and PDZK1 and
in native rat liver membrane extracts. Using PDZK1 knockout mouse liver to further
examine the functional significance of the interaction between PDZK1 and Oatp1a1,
it was found that Oatp1a1 was located predominantly in intracellular structures, in
contrast to its normal basolateral plasma membrane distribution, suggesting a critical
role for oligomerization of Oatp1a1 with PDZK1 for its proper subcellular localization
and function.

= any amino acid and