5-Hydroxymethyl-Furfural and Structurally Related Compounds Block the Ion Conductance in Human Aquaporin-1 Channels and Slow Cancer Cell Migration and Invasion.

Aquaporin-1 (AQP1) dual water and ion channels enhance migration and invasion when upregulated in leading edges of certain classes of cancer cells. Work here identifies structurally related furan compounds as novel inhibitors of AQP1 ion channels. 5-Hydroxymethyl-2-furfural (5HMF), a component of natural medicinal honeys, and three structurally related compounds, 5-nitro-2-furoic acid (5NFA), 5-acetoxymethyl-2-furaldehyde (5AMF), and methyl-5-nitro-2-furoate (M5NF), were analyzed for effects on water and ion channel activities of human AQP1 channels expressed in oocytes.

Combined pharmacological administration of AQP1 ion channel blocker AqB011 and water channel blocker Bacopaside II amplifies inhibition of colon cancer cell migration.

Aquaporin-1 (AQP1) has been proposed as a dual water and cation channel that when upregulated in cancers enhances cell migration rates; however, the mechanism remains unknown. Previous work identified AqB011 as an inhibitor of the gated human AQP1 cation conductance, and bacopaside II as a blocker of AQP1 water pores. In two colorectal adenocarcinoma cell lines, high levels of AQP1 transcript were confirmed in HT29, and low levels in SW480 cells, by quantitative PCR (polymerase chain reaction).

Development of a Photoswitchable Lithium-Sensitive Probe to Analyze Nonselective Cation Channel Activity in Migrating Cancer Cells.

This is the first work to use a newly designed Li-selective photoswitchable probe Sabrina Heng Lithium (SHL) in living colon cancer cells to noninvasively monitor cation channel activity in real time by the appearance of lithium hot spots detected by confocal microscopy. Punctate Li hot spots are clustered in the lamellipodial leading edges of HT29 human colon cancer cells and are colocalized with aquaporin-1 (AQP1) channels. AQP1 is a dual water and cyclic-nucleotide-gated cation channel located in lamellipodia and is essential for rapid cell migration in a subset of aggressive cancers.

Identification of Loop D Domain Amino Acids in the Human Aquaporin-1 Channel Involved in Activation of the Ionic Conductance and Inhibition by AqB011.

Aquaporins are integral proteins that facilitate the transmembrane transport of water and small solutes. In addition to enabling water flux, mammalian Aquaporin-1 (AQP1) channels activated by cyclic GMP can carry non-selective monovalent cation currents, selectively blocked by arylsulfonamide compounds AqB007 (IC 170 μM) and AqB011 (IC 14 μM). models suggested that ligand docking might involve the cytoplasmic loop D (between AQP1 transmembrane domains 4 and 5), but the predicted site of interaction remained to be tested.

Fundamental structural and functional properties of Aquaporin ion channels found across the kingdoms of life.

Aquaporin (AQP) channels in the major intrinsic protein (MIP) family are known to facilitate transmembrane water fluxes in prokaryotes and eukaryotes. Some classes of AQPs also conduct ions, glycerol, urea, CO , nitric oxide, and other small solutes. Ion channel activity has been demonstrated for mammalian AQPs 0, 1, 6, Drosophila Big Brain (BIB), soybean nodulin 26, and rockcress AtPIP2;1.

Divalent Cations Regulate the Ion Conductance Properties of Diverse Classes of Aquaporins.

Aquaporins (AQPs) are known to facilitate water and solute fluxes across barrier membranes. An increasing number of AQPs are being found to serve as ion channels. Ion and water permeability of selected plant and animal AQPs (plant AtPIP2;1, AtPIP2;2, AtPIP2;7, human HsAQP1, rat RnAQP4, RnAQP5, and fly DmBIB) were expressed in oocytes and examined in chelator-buffered salines to evaluate the effects of divalent cations (Ca, Mg, Ba and Cd) on ionic conductances.

Non-selective cation channel activity of aquaporin AtPIP2;1 regulated by Ca and pH.

The aquaporin AtPIP2;1 is an abundant plasma membrane intrinsic protein in Arabidopsis thaliana that is implicated in stomatal closure, and is highly expressed in plasma membranes of root epidermal cells. When expressed in Xenopus laevis oocytes, AtPIP2;1 increased water permeability and induced a non-selective cation conductance mainly associated with Na . A mutation in the water pore, G103W, prevented both the ionic conductance and water permeability of PIP2;1.

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.

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.

Bumetanide Derivatives AqB007 and AqB011 Selectively Block the Aquaporin-1 Ion Channel Conductance and Slow Cancer Cell Migration.

Aquaporins (AQPs) in the major intrinsic family of proteins mediate fluxes of water and other small solutes across cell membranes. AQP1 is a water channel, and under permissive conditions, a nonselective cation channel gated by cGMP. In addition to mediating fluid transport, AQP1 expression facilitates rapid cell migration in cell types including colon cancers and glioblastoma.