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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK079784]; the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant AI057695]; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS062156]; the National Institutes of Health National Institute of General Medical Sciences [Grant GM88824]; and by a postdoctoral fellowship from the Society of Toxicology and Colgate Palmolive (to A.V.D.).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.070607.
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ABBREVIATIONS:
- SLC
- solute carrier
- ABC
- ATP-binding cassette
- Oat
- organic anion transporter
- GWAS
- genome-wide association study
- IS
- indoxyl sulfate
- PG
- prostaglandin
- OR
- olfactory receptor
- PGE2
- prostaglandin E2
- GPCR
- G-protein-coupled receptor.
- Received December 15, 2010.
- Accepted February 11, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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