Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis

Abstract

Organic anion transporters (Oats) are located in the barrier epithelia of diverse organs, where they mediate the absorption and excretion of a wide range of metabolites, signaling molecules, and xenobiotics. Although their interactions with a broad group of substrates have been extensively studied and described, the primary physiological role of Oats remains elusive. The presence of overlapping substrate specificities among the different Oat isoforms, together with recent metabolomic data from the Oat1, Oat3, and renal-specific transporter (RST/URAT1) knockout mice, suggests a possible role in remote signaling wherein substrates excreted through one Oat isoform in one organ are taken up by another Oat isoform located in a different organ, thereby mediating communication between different organ systems, or even between different organisms. Here we further develop this "remote sensing and signaling hypothesis" and suggest how the regulation of SLC22 subfamily members (including those of the organic cation, organic carnitine, and unknown substrate transporter subfamilies) can be better understood by considering the organism's broader need to communicate between epithelial and other tissues by simultaneous regulation of transport of metabolites, signaling molecules, drugs, and toxins. This systems biology perspective of remote signaling (sensing) could help reconcile an enormous array of tissue-specific data for various SLC22 family genes and, possibly, other multispecific transporters, such as those of the organic anion transporting polypeptide (OATP, SLC21) and multidrug resistance-associated protein (MRP) families.

Fig. 1.

Chemosensation between organs/organisms mediated by SLC22 family members. Organic anion transporters (Oats), organic cation transporters (Octs), organic carnitine transporters (Octns), and unknown substrate transporters (Usts) located in the barrier epithelia of certain organs may take up substrates excreted by transporters in other organs (arrows), thus mediating potential remote signaling and therefore communication between organs. This method of communication via the SLC22 transporters can also occur between organisms; for example, odor-type molecules excreted through Oat1 in the urine of cat may be taken up by the Oat6 in the olfactory mucosa of mouse.

Fig. 2.

Potential role of organic anion transporters in homeostasis. By eliminating both endogenous and exogenous toxins, the Oats play a potentially critical role in maintaining whole-body homeostasis. Factors that impair the clearance of substrates by the Oats, such as toxins, ischemia, or competitive inhibition by other substrates, can disrupt Oat function and therefore the efficient exchange of organic anions (Oa) and their counter-ions (Ci) across the membrane. This can eventually lead to perturbed homeostasis. To compensate for the loss of function of other Oats and thereby restore homeostasis, enhanced expression and/or function of the Oats can occur on the transcriptional, translational or post-translational level in either the injured tissues or in other tissues participating in a remote-sensing network.