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The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction

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Abstract

The human SLC6 family is composed of approximately 20 structurally related symporters (co-transporters) that use the transmembrane electrochemical gradient to actively import their substrates into cells. Approximately half of the substrates of these transporters are amino acids, with others transporting biogenic amines and/or closely related compounds, such as nutrients and compatible osmolytes. In this short review, five leaders in the field discuss a number of currently important research themes that involve SLC6 transporters, highlighting the integrative role they play across a wide spectrum of different functions. The first essay, by Gary Rudnick, describes the molecular mechanism of their coupled transport which is being progressively better understood based on new crystal structures, functional studies, and modeling. Next, the question of multiple levels of transporter regulation is discussed by Reinhard Krämer, in the context of osmoregulation and stress response by the related bacterial betaine transporter BetP. The role of selected members of the human SLC6 family that function as nutrient amino acid transporters is then reviewed by François Verrey. He discusses how some of these transporters mediate the active uptake of (essential) amino acids into epithelial cells of the gut and the kidney tubule to support systemic amino acid requirements, whereas others are expressed in specific cells to support their specialized metabolism and/or growth. The most extensively studied members of the human SLC6 family are neurotransmitter reuptake transporters, many of which are important drug targets for the treatment of neuropsychiatric disorders. Randy Blakely discusses the role of posttranscriptional modifications of these proteins in regulating transporter subcellular localization and activity state. Finally, Dennis Murphy reviews how natural gene variants and mouse genetic models display consistent behavioral alterations that relate to altered extracellular neurotransmitter levels.

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Acknowledgments

The laboratory of FV is supported by Swiss NSF grant 31-130471/1 and the National Centre of Competence in Research (NCCR) Kidney.CH, GR by NIH grants DA007259 and DA008213, RDB by NIH awards MH095044, MH07802, MH073159, and MH094527. DLM is funded by the NIMH Intramural Research Program, NIH, Bethesda, MD, USA.

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Authors and Affiliations

  1. Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA

    Gary Rudnick

  2. Institute of Biochemistry, University of Cologne, Cologne, Germany

    Reinhard Krämer

  3. Department of Pharmacology and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA

    Randy D. Blakely

  4. Laboratory of Clinical Science, NIMH-IRP, Bethesda, MD, USA

    Dennis L. Murphy

  5. Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

    Francois Verrey

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  1. Gary Rudnick
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  2. Reinhard Krämer
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  3. Randy D. Blakely
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  4. Dennis L. Murphy
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  5. Francois Verrey
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Correspondence to Francois Verrey.

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Rudnick, G., Krämer, R., Blakely, R.D. et al. The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction. Pflugers Arch - Eur J Physiol 466, 25–42 (2014). https://doi.org/10.1007/s00424-013-1410-1

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  • DOI: https://doi.org/10.1007/s00424-013-1410-1

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