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Molecular Pharmacology

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Toward a Systems Level Understanding of Organic Anion and Other Multispecific Drug Transporters: A Remote Sensing and Signaling Hypothesis

Sun-Young Ahn and Sanjay K. Nigam
Molecular Pharmacology September 2009, 76 (3) 481-490; DOI: https://doi.org/10.1124/mol.109.056564
Sun-Young Ahn
Departments of Pediatrics (S.-Y.A., S.K.N.), Medicine (S.K.N.), and Cellular and Molecular Medicine (S.K.N.), University of California, San Diego, La Jolla, California
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Sanjay K. Nigam
Departments of Pediatrics (S.-Y.A., S.K.N.), Medicine (S.K.N.), and Cellular and Molecular Medicine (S.K.N.), University of California, San Diego, La Jolla, California
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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.

Footnotes

    • Received March 26, 2009.
    • Accepted June 9, 2009.
  • This work was supported by the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant R01-AI057695], the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK079784], and the National Institutes of Health National Institute of Neurological Disorders and Stroke[Grant RO1-NS062156] (all to S.K.N.).

  • ABBREVIATIONS: Oat, organic anion transporter; NSAID, nonsteroidal anti-inflammatory drug; SLC, solute carrier; Oct, organic cation transporter; PAH, para-aminohippurate; TMD, transmembrane domain; PKC, protein kinase C; IS, indoxyl sulfate; HNF, hepatocyte nuclear factor; HEK, human embryonic kidney; PDZ, postsynaptic density 95/disc-large/zona occludens; Urat, uric acid transporter.

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Molecular Pharmacology: 76 (3)
Molecular Pharmacology
Vol. 76, Issue 3
1 Sep 2009
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Toward a Systems Level Understanding of Organic Anion and Other Multispecific Drug Transporters: A Remote Sensing and Signaling Hypothesis

Sun-Young Ahn and Sanjay K. Nigam
Molecular Pharmacology September 1, 2009, 76 (3) 481-490; DOI: https://doi.org/10.1124/mol.109.056564

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Toward a Systems Level Understanding of Organic Anion and Other Multispecific Drug Transporters: A Remote Sensing and Signaling Hypothesis

Sun-Young Ahn and Sanjay K. Nigam
Molecular Pharmacology September 1, 2009, 76 (3) 481-490; DOI: https://doi.org/10.1124/mol.109.056564
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  • Article
    • Abstract
    • Structure and Tissue Distribution of Oats
    • Oat1 and Oat6—A Potential Role in Olfactory Sensing?
    • Oat3 as a Potential Blood Pressure Regulator
    • Role of Oats in Homeostasis—The Effect of Toxins, Ischemia and Substrate Interactions
    • Endogenous and Exogenous Toxins
    • Ischemia/Reperfusion Injury
    • Substrate Interactions
    • Other Physiological Roles
    • Regulation of Oats
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