Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the remote sensing and signaling hypothesis

Abstract

Recent data from knockouts, human disease, and transport studies suggest that solute carrier (SLC) and ATP binding cassette (ABC) multispecific "drug" transporters maintain effective organ and body fluid concentrations of key nutrients, signaling molecules, and antioxidants. These processes involve transcellular movement of solutes across epithelial barriers and fluid compartments (e.g., blood, cerebrospinal fluid, urine, bile) via "matching" or homologous sets of SLC (e.g., SLC21, SLC22, SLC47) and ABC transporters. As described in the "Remote Sensing and Signaling Hypothesis" (Biochem Biophys Res Commun 323:429-436, 2004; Biochem Biophys Res Commun 351:872-876, 2006; J Biol Chem 282:23841-23853, 2007; Nat Clin Pract Nephrol 3:443-448, 2007; Mol Pharmacol 76:481-490, 2009), highly regulated transporter networks with overlapping substrate preferences are involved in sensing and signaling to maintain homeostasis in response to environmental changes (e.g., substrate imbalance and injury). They function in parallel with (and interact with) the endocrine and autonomic systems. Uric acid (urate), carnitine, prostaglandins, conjugated sex steroids, cGMP, odorants, and enterobiome metabolites are discussed here as examples. Xenobiotics hitchhike on endogenous carrier systems, sometimes leading to toxicity and side effects. By regulation of the expression and/or function of various remote organ multispecific transporters after injury, the overall transport capacity of the remote organ to handle endogenous toxins, metabolites, and signaling molecules may change, aiding in recovery. Moreover, these transporters may play a role in communication between organisms. The specific cellular components involved in sensing and altering transporter abundance or functionality depend upon the metabolite in question and probably involve different types of sensors as well as epigenetic regulation.

Fig. 1.

Diagram depicting the remote sensing and signaling mechanism among organs mediating urate handling. Urate is either absorbed in the intestine or synthesized in the liver. Its absorption, distribution, and excretion are mediated by a battery of solute carriers in individual organs to achieve balance and homeostasis in the cell, organ, and at the system level.

Fig. 2.

l-Carnitine and its carrier SLC22A5 mediated sensing and signaling among organs and between mother and infant. Liver is the primary site of l-carnitine biosynthesis. Circulating l-carnitine is distributed/transported through its carriers, primarily SLC22A5, depicted here, as well as Oct3, Flipt1 and Flipt2 (CT1/SLC22A15 and CT2/SLC22A16) and others to the target organs. The synthesis and distribution of l-carnitine is regulated physiologically. For example, during lactation, l-carnitine is preferentially distributed to the nursing mother's breast through increased expression of its carriers at the expense of the liver, because mother's milk is the only source of carnitine for the infant and is essential for the survival/growth of the baby.

Fig. 3.

Diagram depicting iterative enzymatic- and transporter-mediated organic anion solute handling in intestine and in liver.

Fig. 4.

Flow diagram depicting distribution and handling of enterobiome metabolites by solute carriers.

Fig. 5.

The solute carrier-mediated remote sensing and signaling mechanism of solute handling maintains balance and homeostasis at multiple levels. This process resembles other regulatory mechanisms of autonomous nervous systems and endocrine systems.

Fig. 6.

Speculative diagram of roles of odorant transporters such as Oats (Oat6) in proposed remote communication. The odorants/volatile steroid derivatives from the environment (including intra- and interspecies sensing) can be, after eliciting an odorant response (via odorant receptors) in the olfactory mucosa, recycled/delivered to internal organs to trigger remote responses. We speculate that these responses might be manifested as neuronal signaling, perhaps in the limbic system, or a signaling response in a remote organ (testis, adrenal gland, liver, kidney, etc.) mediated by nonolfactory odorant receptors. These signaling molecules can conceivably then be excreted by kidney, large intestine, or sweat gland, where they can potentially be involved in the subsequent round of remote sensing. The handling of these molecules is dependent on the combination of SLC and ABC transporters and their localization and expression.

Fig. 7.

Diagram depicting solute carrier-mediated communication within cell, between organs, between individuals of the same species, and between individuals of different species.