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PMID: 11487521 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Phloretin differentially inhibits volume-sensitive and cyclic AMP-activated, but not Ca-activated, Cl(-) channels.

British journal of pharmacology ·Vol. 133 ·No. 7 ·2001-08-00 ·Pages 1096-106

Fan HT, Morishima S, Kida H, Okada Y

Abstract

Some phenol derivatives are known to block volume-sensitive Cl(-) channels. However, effects on the channel of the bisphenol phloretin, which is a known blocker of glucose uniport and anion antiport, have not been examined. In the present study, we investigated the effects of phloretin on volume-sensitive Cl(-) channels in comparison with cyclic AMP-activated CFTR Cl(-) channels and Ca(2+)-activated Cl(-) channels using the whole-cell patch-clamp technique. Extracellular application of phloretin (over 10 microM) voltage-independently, and in a concentration-dependent manner (IC(50) approximately 30 microM), inhibited the Cl(-) current activated by a hypotonic challenge in human epithelial T84, Intestine 407 cells and mouse mammary C127/CFTR cells. In contrast, at 30 microM phloretin failed to inhibit cyclic AMP-activated Cl(-) currents in T84 and C127/CFTR cells. Higher concentrations (over 100 microM) of phloretin, however, partially inhibited the CFTR Cl(-) currents in a voltage-dependent manner. At 30 and 300 microM, phloretin showed no inhibitory effect on Ca(2+)-dependent Cl(-) currents induced by ionomycin in T84 cells. It is concluded that phloretin preferentially blocks volume-sensitive Cl(-) channels at low concentrations (below 100 microM) and also inhibits cyclic AMP-activated Cl(-) channels at higher concentrations, whereas phloretin does not inhibit Ca(2+)-activated Cl(-) channels in epithelial cells.

MeSH Terms
Animals Calcium/pharmacology Cell Size/drug effects,physiology Chloride Channels/drug effects,physiology Cyclic AMP/pharmacology Dose-Response Relationship, Drug Humans Hypotonic Solutions/pharmacology Ionomycin/pharmacology Ionophores/pharmacology Isotonic Solutions/pharmacology Membrane Potentials/drug effects Patch-Clamp Techniques Phloretin/pharmacology Tumor Cells, Cultured
Chemicals
Chloride Channels Hypotonic Solutions Ionophores Isotonic Solutions Ionomycin Cyclic AMP Phloretin Calcium
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Fan H T
Department of Cell Physiology, National Institute for Physiological Sciences, Myodaiji-cho, Okazaki 444-8585, Japan.
Morishima S
Kida H
Okada Y
References (70)
70 references, click to expand
  1. Volume expansion-sensing outward-rectifier Cl- channel: fresh start to the molecular identity and volume sensor.
    Am J Physiol. 1997 Sep;273(3 Pt 1):C755-89 PMID: 9316396
  2. Molecular identification of a volume-regulated chloride channel.
    Nature. 1997 Nov 27;390(6658):417-21 PMID: 9389484
  3. Inactivation of calcium-activated chloride channels in smooth muscle by calcium/calmodulin-dependent protein kinase.
    Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14918-23 PMID: 9405714
  4. Progressive effects of phloridzin on melanogenesis in B16 mouse melanoma cells.
    Biosci Biotechnol Biochem. 1997 Dec;61(12):1963-7 PMID: 9438975
  5. Heterogenous expression of Ca2+-dependent K+ currents by Müller glial cells.
    Neuroreport. 1997 Dec 22;8(18):3841-5 PMID: 9462452
  6. Properties of volume-regulated anion channels in mammalian cells.
    Prog Biophys Mol Biol. 1997;68(1):69-119 PMID: 9481145
  7. Calcium and phospholipid-dependent protein kinase activity in mouse epidermis cytosol. Stimulation by complete and incomplete tumor promoters and inhibition by various compounds.
    Biochem Biophys Res Commun. 1984 Oct 15;124(1):63-8 PMID: 6238597
  8. Interactions of inhibitors on anion transporter of human erythrocyte.
    Am J Physiol. 1987 Feb;252(2 Pt 1):C153-62 PMID: 3826335
  9. Ca2+ sensitivity of volume-regulatory K+ and Cl- channels in cultured human epithelial cells.
    J Physiol. 1988 Aug;402:687-702 PMID: 2466988
  10. Membrane mechanisms in volume and pH regulation in vertebrate cells.
    Physiol Rev. 1989 Apr;69(2):315-82 PMID: 2538851
  11. Calphostin C (UCN-1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase C.
    Biochem Biophys Res Commun. 1989 Mar 15;159(2):548-53 PMID: 2467670
  12. A volume-sensitive chloride conductance in human colonic cell line T84.
    Am J Physiol. 1989 Jun;256(6 Pt 1):C1111-9 PMID: 2472065
  13. Separate Cl- conductances activated by cAMP and Ca2+ in Cl(-)-secreting epithelial cells.
    Proc Natl Acad Sci U S A. 1990 Jul;87(13):4956-60 PMID: 2164213
  14. Stretch-induced activation of Ca2(+)-permeable ion channels is involved in the volume regulation of hypotonically swollen epithelial cells.
    Neurosci Res Suppl. 1990;12:S5-13 PMID: 2173819
  15. Biphasic rises in cytosolic free Ca2+ in association with activation of K+ and Cl- conductance during the regulatory volume decrease in cultured human epithelial cells.
    Pflugers Arch. 1990 Aug;416(6):710-4 PMID: 2247343
  16. Activation of chloride channels in normal and cystic fibrosis airway epithelial cells by multifunctional calcium/calmodulin-dependent protein kinase.
    Nature. 1991 Feb 28;349(6312):793-6 PMID: 1705665
  17. CaMKII mediates stimulation of chloride conductance by calcium in T84 cells.
    Am J Physiol. 1991 Apr;260(4 Pt 1):C877-82 PMID: 1708204
  18. Phosphorylation-regulated Cl- channel in CHO cells stably expressing the cystic fibrosis gene.
    Nature. 1991 Aug 15;352(6336):628-31 PMID: 1714039
  19. Phloretin affects the fast potassium channels in frog nerve fibres.
    Eur Biophys J. 1991;20(2):79-86 PMID: 1935816
  20. Antibody against a cystic fibrosis transmembrane conductance regulator-derived synthetic peptide inhibits anion currents in human colonic cell line T84.
    J Biol Chem. 1992 Apr 25;267(12):8411-6 PMID: 1373728
  21. Volume-sensitive chloride conductance in bovine chromaffin cell membrane.
    J Physiol. 1992 Apr;449:197-218 PMID: 1326043
  22. The effect of phloretin on single potassium channels in myelinated nerve.
    Eur Biophys J. 1992;21(2):93-7 PMID: 1396407
  23. Calcium signaling in cell volume regulation.
    Physiol Rev. 1992 Oct;72(4):1037-61 PMID: 1332089
  24. Volume-regulatory Cl- channel currents in cultured human epithelial cells.
    J Physiol. 1992 Oct;456:351-71 PMID: 1284079
  25. Cell volume regulation in human neutrophils: 2-(aminomethyl)phenols as Cl- channel inhibitors.
    Am J Physiol. 1993 Jul;265(1 Pt 1):C143-55 PMID: 8393278
  26. Mechanism and regulation of swelling-activated inositol efflux in brain glial cells.
    Am J Physiol. 1993 Jul;265(1 Pt 1):C244-56 PMID: 8393281
  27. Activating effect of the flavonoid phloretin on Ca(2+)-activated K+ channels in myelinated nerve fibers of Xenopus laevis [corrected].
    Neurosci Lett. 1994 Jan 3;165(1-2):167-70 PMID: 8015719
  28. Molecular cloning and expression of a member of the aquaporin family with permeability to glycerol and urea in addition to water expressed at the basolateral membrane of kidney collecting duct cells.
    Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6269-73 PMID: 7517548
  29. Ketoconazole blocks organic osmolyte efflux independently of its effect on arachidonic acid conversion.
    Am J Physiol. 1994 Jul;267(1 Pt 1):C266-71 PMID: 7519397
  30. Dissociation of depolarization-activated and swelling-activated Cl- channels.
    Am J Physiol. 1994 Aug;267(2 Pt 1):C642-9 PMID: 8074197
  31. Ca(2+)-mobilizing hormones potentiate hypotonicity-induced activation of ionic conductances in Intestine 407 cells.
    Am J Physiol. 1994 Nov;267(5 Pt 1):C1271-8 PMID: 7977690
  32. Hypotonically activated chloride current in HSG cells.
    J Membr Biol. 1994 Nov;142(2):181-93 PMID: 7884810
  33. Gonadotropin-releasing hormone induced Ca2+ influx in nonsecreting pituitary adenoma cells: role of voltage-dependent Ca2+ channels and protein kinase C.
    Mol Cell Neurosci. 1994 Dec;5(6):699-708 PMID: 7704445
  34. Cell swelling activates separate taurine and chloride channels in Ehrlich mouse ascites tumor cells.
    J Membr Biol. 1994 Dec;142(3):289-98 PMID: 7535853
  35. Protein kinase C regulates the magnitude and stability of CFTR currents in pancreatic duct cells.
    Am J Physiol. 1995 Apr;268(4 Pt 1):C823-8 PMID: 7537451
  36. Properties of volume-sensitive Cl- channels in a human epithelial cell line.
    Jpn J Physiol. 1994;44 Suppl 2:S31-5 PMID: 7752549
  37. Volume-sensitive taurine transport in bovine articular chondrocytes.
    J Physiol. 1995 May 1;484 ( Pt 3):755-66 PMID: 7623290
  38. Inhibition of Ca(2+)-dependent Cl- channels from secretory epithelial cells by low internal pH.
    J Membr Biol. 1995 Sep;147(1):95-104 PMID: 8531203
  39. Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor.
    Nat Genet. 1996 Mar;12(3):280-7 PMID: 8589719
  40. Osmoregulatory alterations in myo-inositol uptake by bovine lens epithelial cells. Part 5. Mechanism of the myo-inositol efflux pathway.
    Invest Ophthalmol Vis Sci. 1996 Mar;37(4):619-29 PMID: 8595962
  41. Halide and alkyl phenols block volume-sensitive chloride channels in human glial cells (U-138MG).
    J Membr Biol. 1998 Apr 1;162(3):191-200 PMID: 9543491
  42. Characterization of a rat Na+-dicarboxylate cotransporter.
    J Biol Chem. 1998 Aug 14;273(33):20972-81 PMID: 9694847
  43. Distinct Ca2+- and cAMP-dependent anion conductances in the apical membrane of polarized T84 cells.
    Am J Physiol. 1998 Aug;275(2 Pt 1):C484-95 PMID: 9688603
  44. Criteria for the molecular identification of the volume-sensitive outwardly rectifying Cl- channel.
    J Gen Physiol. 1998 Sep;112(3):365-7 PMID: 9725895
  45. Molecular characterization of a broad selectivity neutral solute channel.
    J Biol Chem. 1998 Sep 18;273(38):24737-43 PMID: 9733774
  46. Tyrosine kinase-independent extracellular action of genistein on the CFTR Cl- channel in guinea pig ventricular myocytes and CFTR-transfected mouse fibroblasts.
    Jpn J Physiol. 1998 Oct;48(5):389-96 PMID: 9852348
  47. Swelling-induced taurine release without chloride channel activity in Xenopus laevis oocytes expressing anion channels and transporters.
    Biochim Biophys Acta. 2000 Jul 31;1467(1):91-100 PMID: 10930512
  48. Active glucose uptake by strips of guinea pig intestine; competitive inhibition by phlorhizin and phloretin.
    Can J Biochem. 1965 Jul;43(7):851-8 PMID: 5855659
  49. Inhibition of glucose transport into brain by phlorizin, phloretin and glucose analogues.
    Biochim Biophys Acta. 1975 Nov 3;406(4):505-15 PMID: 1182174
  50. Effects of the dipolar form of phloretin on potassium conductance in squid giant axons.
    Biophys J. 1980 Aug;31(2):229-46 PMID: 6266534
  51. CFTR is a conductance regulator as well as a chloride channel.
    Physiol Rev. 1999 Jan;79(1 Suppl):S145-66 PMID: 9922379
  52. CFTR, a regulator of channels.
    J Membr Biol. 1999 Mar 1;168(1):1-8 PMID: 10051684
  53. Separate taurine and chloride efflux pathways activated during regulatory volume decrease.
    Am J Physiol. 1999 Sep;277(3 Pt 1):C392-402 PMID: 10484326
  54. Biochemistry of natural pigments; (exclusive of haeme pigments and carotenoids).
    Annu Rev Biochem. 1951;20:487-512 PMID: 14847538
  55. Swelling-activated, cystic fibrosis transmembrane conductance regulator-augmented ATP release and Cl- conductances in murine C127 cells.
    J Physiol. 2000 Feb 15;523 Pt 1:1-11 PMID: 10673540
  56. Further evidence for the existence of a volume-activated taurine efflux pathway in rat mammary tissue independent from volume-sensitive Cl- channels.
    Acta Physiol Scand. 2000 Feb;168(2):295-9 PMID: 10712567
  57. Involvement of K(Ca) channels and stretch-activated channels in calcium influx, triggering membrane fusion of chick embryonic myoblasts.
    Dev Biol. 1996 Apr 10;175(1):14-23 PMID: 8608860
  58. Cellular and molecular physiology of volume-sensitive anion channels.
    Am J Physiol. 1996 Mar;270(3 Pt 1):C711-30 PMID: 8638650
  59. Expression of the rat GLUT1 glucose transporter in the yeast Saccharomyces cerevisiae.
    Biochem J. 1996 Apr 1;315 ( Pt 1):177-82 PMID: 8670104
  60. Characterization of volume-activated chloride currents in endothelial cells from bovine pulmonary artery.
    J Membr Biol. 1996 Feb;149(3):189-97 PMID: 8801351
  61. Swelling and Ca2+-activated anion conductances in C127 epithelial cells expressing WT and delta F508-CFTR.
    J Membr Biol. 1996 Jun;151(3):269-78 PMID: 8661514
  62. Effects of channel modulators on cloned large-conductance calcium-activated potassium channels.
    Mol Pharmacol. 1996 Jul;50(1):206-17 PMID: 8700114
  63. Blockade of swelling-induced chloride channels by phenol derivatives.
    Br J Pharmacol. 1996 May;118(1):41-8 PMID: 8733574
  64. Voltage-dependent inactivation of volume-regulated Cl- current in human T84 colonic and B-cell myeloma cell lines.
    Pflugers Arch. 1995 Dec;431(2):297-9 PMID: 9026791
  65. Selectivity of the renal collecting duct water channel aquaporin-3.
    J Biol Chem. 1996 Oct 11;271(41):25079-82 PMID: 8810261
  66. The chloride current induced by expression of the protein pICln in Xenopus oocytes differs from the endogenous volume-sensitive chloride current.
    J Physiol. 1996 Sep 1;495 ( Pt 2):441-7 PMID: 8887755
  67. Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A.
    J Biol Chem. 1997 Feb 21;272(8):4978-84 PMID: 9030559
  68. Volume regulation in NIH/3T3 cells not expressing P-glycoprotein. II. Chloride and amino acid fluxes.
    Am J Physiol. 1997 Jun;272(6 Pt 1):C1804-9 PMID: 9227408
  69. Regulatory volume decrease of cardiac myocytes induced by beta-adrenergic activation of the Cl- channel in guinea pig.
    J Gen Physiol. 1997 Jul;110(1):73-82 PMID: 9234172
  70. Cystic fibrosis transmembrane conductance regulator activates water conductance in Xenopus oocytes.
    Pflugers Arch. 1997 Nov;434(6):841-7 PMID: 9306020
Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1038/sj.bjp.0704159
Published
2001-08-00
Pages
1096-106
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1572865
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.bjp.0704159 PMC Full Text View journal details
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