title: 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.
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.
authors.affiliation: 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.).
authors.forename: Jinxin V
authors.initials: JV
authors.lastname: Pei
authors.affiliation: 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.).
authors.forename: Mohamad
authors.initials: M
authors.lastname: Kourghi
authors.affiliation: 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.).
authors.forename: Michael L
authors.initials: ML
authors.lastname: De Ieso
authors.affiliation: 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.).
authors.forename: Ewan M
authors.initials: EM
authors.lastname: Campbell
authors.affiliation: 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.).
authors.forename: Hilary S
authors.initials: HS
authors.lastname: Dorward
authors.affiliation: 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.).
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Hardingham
authors.affiliation: 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.) andrea.yool@adelaide.edu.au.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Yool
mesh_terms: D000818:Animals; D051398:Aquaporin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034681:Bacopa; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D009995:Osmosis / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D010946:Plants, Medicinal; D012503:Saponins / Q000737:chemistry* / Q000494:pharmacology*; D013997:Time Factors; D059008:Time-Lapse Imaging; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D007473:Ion Channels; D010936:Plant Extracts; D012503:Saponins; D014315:Triterpenes; D051398:Aquaporin 1; C442170:bacopaside I; D006152:Cyclic GMP; C442169:bacopaside II