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Molecular Pharmacology

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Research ArticleMinireview

Remote Communication through Solute Carriers and ATP Binding Cassette Drug Transporter Pathways: An Update on the Remote Sensing and Signaling Hypothesis

Wei Wu, Ankur V. Dnyanmote and Sanjay K. Nigam
Molecular Pharmacology May 2011, 79 (5) 795-805; DOI: https://doi.org/10.1124/mol.110.070607
Wei Wu
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Ankur V. Dnyanmote
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Sanjay K. Nigam
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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.

  • 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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Molecular Pharmacology: 79 (5)
Molecular Pharmacology
Vol. 79, Issue 5
1 May 2011
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Research ArticleMinireview

Remote Communication through Solute Carriers and ATP Binding Cassette Drug Transporter Pathways: An Update on the Remote Sensing and Signaling Hypothesis

Wei Wu, Ankur V. Dnyanmote and Sanjay K. Nigam
Molecular Pharmacology May 1, 2011, 79 (5) 795-805; DOI: https://doi.org/10.1124/mol.110.070607

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Research ArticleMinireview

Remote Communication through Solute Carriers and ATP Binding Cassette Drug Transporter Pathways: An Update on the Remote Sensing and Signaling Hypothesis

Wei Wu, Ankur V. Dnyanmote and Sanjay K. Nigam
Molecular Pharmacology May 1, 2011, 79 (5) 795-805; DOI: https://doi.org/10.1124/mol.110.070607
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  • Article
    • Abstract
    • Introduction
    • Urate Handling
    • Carnitine Handling
    • Enterobiome Metabolite Handling between Organs
    • Implications of Toxin Sensing and Handling in Tissue Injury
    • Interaction of SLC and ABC Transporters with Other Signaling Pathways
    • Perspective on Remote Signaling via SLC and ABC Transporters
    • Intra- and Interspecies Sensing and Handling of Signaling Molecules
    • Summary
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