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Research ArticleArticle

Differential Inhibition of Water and Ion Channel Activities of Mammalian Aquaporin-1 by Two Structurally Related Bacopaside Compounds Derived from the Medicinal Plant Bacopa monnieri

Jinxin V. Pei, Mohamad Kourghi, Michael L. De Ieso, Ewan M. Campbell, Hilary S. Dorward, Jennifer E. Hardingham and Andrea J. Yool
Molecular Pharmacology October 2016, 90 (4) 496-507; DOI: https://doi.org/10.1124/mol.116.105882
Jinxin V. Pei
School of Medicine (J.V.P., M.K., M.L.D.I., J.E.H., A.J.Y.), and Institute for Photonics and Advanced Sensing (J.V.P., A.J.Y.), University of Adelaide, Adelaide, Australia; School of Biological Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom (E.M.C.); Molecular Oncology Laboratory, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville, Australia (H.S.D., J.E.H.)
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Mohamad Kourghi
School of Medicine (J.V.P., M.K., M.L.D.I., J.E.H., A.J.Y.), and Institute for Photonics and Advanced Sensing (J.V.P., A.J.Y.), University of Adelaide, Adelaide, Australia; School of Biological Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom (E.M.C.); Molecular Oncology Laboratory, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville, Australia (H.S.D., J.E.H.)
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Michael L. De Ieso
School of Medicine (J.V.P., M.K., M.L.D.I., J.E.H., A.J.Y.), and Institute for Photonics and Advanced Sensing (J.V.P., A.J.Y.), University of Adelaide, Adelaide, Australia; School of Biological Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom (E.M.C.); Molecular Oncology Laboratory, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville, Australia (H.S.D., J.E.H.)
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Ewan M. Campbell
School of Medicine (J.V.P., M.K., M.L.D.I., J.E.H., A.J.Y.), and Institute for Photonics and Advanced Sensing (J.V.P., A.J.Y.), University of Adelaide, Adelaide, Australia; School of Biological Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom (E.M.C.); Molecular Oncology Laboratory, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville, Australia (H.S.D., J.E.H.)
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Hilary S. Dorward
School of Medicine (J.V.P., M.K., M.L.D.I., J.E.H., A.J.Y.), and Institute for Photonics and Advanced Sensing (J.V.P., A.J.Y.), University of Adelaide, Adelaide, Australia; School of Biological Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom (E.M.C.); Molecular Oncology Laboratory, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville, Australia (H.S.D., J.E.H.)
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Jennifer E. Hardingham
School of Medicine (J.V.P., M.K., M.L.D.I., J.E.H., A.J.Y.), and Institute for Photonics and Advanced Sensing (J.V.P., A.J.Y.), University of Adelaide, Adelaide, Australia; School of Biological Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom (E.M.C.); Molecular Oncology Laboratory, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville, Australia (H.S.D., J.E.H.)
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Andrea J. Yool
School of Medicine (J.V.P., M.K., M.L.D.I., J.E.H., A.J.Y.), and Institute for Photonics and Advanced Sensing (J.V.P., A.J.Y.), University of Adelaide, Adelaide, Australia; School of Biological Sciences, University of Aberdeen, Aberdeen, Scotland, United Kingdom (E.M.C.); Molecular Oncology Laboratory, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville, Australia (H.S.D., J.E.H.)
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Abstract

Aquaporin-1 (AQP1) is a major intrinsic protein that facilitates flux of water and other small solutes across cell membranes. In addition to its function as a water channel in maintaining fluid homeostasis, AQP1 also acts as a nonselective cation channel gated by cGMP, a property shown previously to facilitate rapid cell migration in a AQP1-expressing colon cancer cell line. Here we report two new modulators of AQP1 channels, bacopaside I and bacopaside II, isolated from the medicinal plant Bacopa monnieri. Screening was conducted in the Xenopus oocyte expression system, using quantitative swelling and two-electrode voltage clamp techniques. Results showed bacopaside I blocked both the water (IC50 117 μM) and ion channel activities of AQP1 but did not alter AQP4 activity, whereas bacopaside II selectively blocked the AQP1 water channel (IC50 18 μM) without impairing the ionic conductance. These results fit with predictions from in silico molecular modeling. Both bacopasides were tested in migration assays using HT29 and SW480 colon cancer cell lines, with high and low levels of AQP1 expression, respectively. Bacopaside I (IC50 48 μM) and bacopaside II (IC50 14 μM) impaired migration of HT29 cells but had minimal effect on SW480 cell migration. Our results are the first to identify differential AQP1 modulators isolated from a medicinal plant. Bacopasides could serve as novel lead compounds for pharmaceutic development of selective aquaporin modulators.

Footnotes

    • Received July 3, 2016.
    • Accepted July 26, 2016.
  • This work was supported by funding from the University of Adelaide Institute for Photonics and Advanced Sensing 2015 Pilot Grant program, and Australian Research Council Discovery Project grant DP160104641.

  • dx.doi.org/10.1124/mol.116.105882.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 90 (4)
Molecular Pharmacology
Vol. 90, Issue 4
1 Oct 2016
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Research ArticleArticle

Inhibition of Aquaporin-1 by Bacopasides

Jinxin V. Pei, Mohamad Kourghi, Michael L. De Ieso, Ewan M. Campbell, Hilary S. Dorward, Jennifer E. Hardingham and Andrea J. Yool
Molecular Pharmacology October 1, 2016, 90 (4) 496-507; DOI: https://doi.org/10.1124/mol.116.105882

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Research ArticleArticle

Inhibition of Aquaporin-1 by Bacopasides

Jinxin V. Pei, Mohamad Kourghi, Michael L. De Ieso, Ewan M. Campbell, Hilary S. Dorward, Jennifer E. Hardingham and Andrea J. Yool
Molecular Pharmacology October 1, 2016, 90 (4) 496-507; DOI: https://doi.org/10.1124/mol.116.105882
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