NAD(P)H Oxidase-derived H2O2 Signals Chloride Channel Activation in Cell Volume Regulation and Cell Proliferation

Cellular swelling triggers the activation of Cl– channels (volume-sensitive outwardly rectifying (VSOR) Cl– channels) in many cell types. Ensuing regulatory volume decrease has been considered the primary function of these channels. However, Cl– channels, which share functional properties with volume-sensitive Cl– channels, have been shown to be involved in other physiological processes, including cell proliferation and apoptosis, raising the question of their physiological roles and the signal transduction pathways involved in their activation. Here we report that exogenously applied H2O2 elicited VSOR Cl– channel activation. Furthermore, activation of these channels was found to be coupled to NAD(P)H oxidase activity. Also, epidermal growth factor, known to increase H2O2 production, activated Cl– channels with properties identical to swelling-sensitive Cl– channels. It is concluded that NAD(P)H oxidase-derived H2O2 is the common signal transducing molecule that mediates the activation of these ubiquitously expressed anion channels under a variety of physiological conditions. Cellular swelling triggers the activation of Cl– channels (volume-sensitive outwardly rectifying (VSOR) Cl– channels) in many cell types. Ensuing regulatory volume decrease has been considered the primary function of these channels. However, Cl– channels, which share functional properties with volume-sensitive Cl– channels, have been shown to be involved in other physiological processes, including cell proliferation and apoptosis, raising the question of their physiological roles and the signal transduction pathways involved in their activation. Here we report that exogenously applied H2O2 elicited VSOR Cl– channel activation. Furthermore, activation of these channels was found to be coupled to NAD(P)H oxidase activity. Also, epidermal growth factor, known to increase H2O2 production, activated Cl– channels with properties identical to swelling-sensitive Cl– channels. It is concluded that NAD(P)H oxidase-derived H2O2 is the common signal transducing molecule that mediates the activation of these ubiquitously expressed anion channels under a variety of physiological conditions. Volume-activated Cl– channels have been widely studied in their role as regulators of normal cell volume (for review, see Refs. 1Hoffmann E.K. Simonsen L.O. Physiol. Rev. 1989; 69: 315-382Google Scholar and 2Strange K. Jackson P.S. Kidney Int. 1995; 48: 994-1003Google Scholar). However, these channels are increasingly found to be involved in other physiological processes, including cell proliferation. (3Shen M.R. Droogmans G. Eggermont J. Voets T. Ellory J.C. Nilius B. J. Physiol. (Lond.). 2000; 529: 385-394Google Scholar) and apoptosis (4Szabo I. Lepple-Wienhues A. Kaba K.N. Zoratti M. Gulbins E. Lang F. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6169-6174Google Scholar). In general, cells produce O2·¯ that is rapidly converted into H2O2 and its generation is modulated by activation of cell surface receptors, stress responses, and apoptosis (5Rhee S.G. Bae Y.S. Lee S.R. Kwon J. Science's STKE. 2000; http://stke.sciencemag.org/cgi/content/full/sigtrans;2000/53/pe1Google Scholar, 6Johnson T.M. Yu Z.X. Ferrans V.J. Lowenstein R.A. Finkel T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 11848-11852Google Scholar). A fundamental enzyme involved in this process is NAD(P)H oxidase, which was first described in neutrophils. A number of NAD(P)H oxidases-related enzymes were later identified in nonphagocytic cells and some of them are associated to H2O2 production in response to ligands and peptide growth factors (7Lambeth J.D. Curr. Opin. Hematol. 2002; 9: 11-17Google Scholar). Although H2O2 is also known to be produced by xanthine oxidase, NO synthase, and cytochrome P450, as well as the mitochondria, there is no compelling evidence linking them to cell surface receptor activation. It is well documented that addition of exogenous H2O2 or increased intracellular generation of H2O2 influences the function of various proteins, including protein-tyrosine phosphatases, protein kinases, and transcription factors, suggesting that H2O2 might be an intracellular messenger (8Finkel T. Curr. Opin. Cell Biol. 1998; 10: 248-253Google Scholar, 9Suzuki Y.J. Ford G.D. J. Mol. Cell Cardiol. 1999; 31: 345-353Google Scholar, 10Rhee S.G. Exp. Mol. Med. 1999; 31: 53-59Google Scholar).Cells activate VSOR 1The abbreviations used are: VSOR, volume-sensitive outwardly rectifying; DPI, diphenylene iodonium chloride; Tiron, 4,5-dihydroxy-1,3-benzene disulfonic acid; PTP, protein-tyrosine phosphatase; PTK, protein-tyrosine kinase; DTT, dithiothreitol; EGF, epidermal growth factor. 1The abbreviations used are: VSOR, volume-sensitive outwardly rectifying; DPI, diphenylene iodonium chloride; Tiron, 4,5-dihydroxy-1,3-benzene disulfonic acid; PTP, protein-tyrosine phosphatase; PTK, protein-tyrosine kinase; DTT, dithiothreitol; EGF, epidermal growth factor. Cl– channels in response to an increase in cell volume (11Hoffmann E.K. Lambert I.H. Simonsen L.O. Renal Physiol. Biochem. 1988; 11: 221-247Google Scholar, 12Okada Y. Am. J. Physiol. 1997; 273: C755-C789Google Scholar, 13Stutzin A. Torres R. Oporto M. Pacheco P. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1999; 277: C392-C402Google Scholar). These channels are also found to be activated under conditions in which cell volume is constant (14Doroshenko P. Penner R. Neher E. J. Physiol. (Lond.). 1991; 436: 711-724Google Scholar, 15Schumacher P.A. Sakellaropoulos G. Phipps D.J. Schlichter L.C. J. Biol. 1995; Scholar, T. Droogmans G. Nilius B. J. Physiol. (Lond.). 1996; evidence their in a variety of other cell volume VSOR Cl– channel is modulated cell S. J. P. B. Am. J. Physiol. 2002; and proliferation in cells is by these channels R. M. J. Physiol. (Lond.). Scholar). channels are also to a role in of have been shown to activation of outwardly rectifying Cl– channels (4Szabo I. Lepple-Wienhues A. Kaba K.N. Zoratti M. Gulbins E. Lang F. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6169-6174Google which were also activated by swelling A. I. T. Kaba Gulbins E. Lang F. J. Cell Biol. 1998; Scholar). is by of cells volume E. Y. T. A. Y. Proc. Natl. Acad. Sci. U. S. A. 2000; Scholar, Am. J. Physiol. 1996; and of VSOR Cl– channels volume decrease Y. E. Biochem. Physiol. A Mol. Physiol. these channels are activated under many we a common that mediates activation of VSOR Cl– channels. In the the question of H2O2 mediates VSOR Cl– channel activation was in cell that H2O2 is a common messenger in VSOR Cl– channel activation in cell volume and cell and and cells were as described A. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1997; 273: Scholar). cells were and the of an with and with was with to and with and an of were by In was used of as and was by the the various were the B. of Scholar). in were J. and were were the of R. A. J. Physiol. 1991; Scholar). was and the were was as described A. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1997; 273: of Cell in cell volume were in cells by in of an as described A. Torres R. Oporto M. Pacheco P. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1999; 277: C392-C402Google Scholar, J. 1995; of Cellular H2O2 and and by the cells was by a coupled and as R. Biol. Med. Scholar, E. Science's STKE. and of the J. J. 1995; Scholar) was into the an of the protein to the P. 2000; Scholar). cells were with of the to the were in which and 4,5-dihydroxy-1,3-benzene disulfonic were cells were as described Y. J. M. J. Biol. 2000; Scholar). In the of diphenylene iodonium was of the was by and considered VSOR Cl– of cells a cell to H2O2 in activated an outwardly rectifying Cl– with a of the of and was to that elicited by a in to its and Cl– as by the in in anion of the channels activated by H2O2 the Cl– anion and the described VSOR Cl– channels B. Eggermont J. Voets T. G. Droogmans G. Mol. Biol. 1997; Scholar). the of the Cl– was addition of H2O2 with a constant of was H2O2 with an constant to These that addition of H2O2 to cells the activation of a Cl– in the of cell swelling that is the Cl– the of a known VSOR Cl– channel the channels activated by a of the Cl– Furthermore, to a a to the Cl– channels in many cell also Cl– by suggesting that the anion channels activated by H2O2 are the as the channels activated by cell swelling NAD(P)H H2O2 in H2O2 is VSOR Cl– channel be that cells increase intracellular to a increase in intracellular as by a coupled and as an of cell to a a in H2O2 the first by a decrease in H2O2 increase in H2O2 production was the of the and was under or conditions role of NAD(P)H oxidase in the H2O2 generation was In cells with a NAD(P)H oxidase H2O2 production was by that H2O2 a NAD(P)H These are in with the increase in in I.H. J. Biol. H2O2 production is activation of volume-sensitive channels. the in H2O2 produced by the cells a in and cells was as described under the production of H2O2 in as well as in were and cells and conditions. of Tiron, and VSOR Cl– channels. are expressed as of Cl– cells were with and and to or was in the in to the cells to or Cl– H2O2 increased H2O2 production under conditions activation of the Cl– we the activation of this Cl– H2O2 of cells with the Cl– by the Cl– the that H2O2 is involved in the activation of VSOR Cl– channels. In with these the in cells the NAD(P)H oxidase is an outwardly rectifying Cl– of the Cl– J. Physiol. 2002; Scholar). A of H2O2 generation is the of by the NAD(P)H oxidase to which is or converted to we studied the of the O2·¯ the activation of VSOR Cl– channels. of cells with the Cl– the Cl– that O2·¯ production and to H2O2 are VSOR Cl– channel activation. Cl– channel activation was by H2O2 and by other we in cells by the of the enzyme of H2O2 to cells with the Cl– and that VSOR Cl– channel activation is H2O2 and other of the cells with a elicited a Cl– with properties to that by H2O2 evidence that H2O2 its as a messenger by as that in the found in the of protein-tyrosine Rev. 1998; Scholar, A. A. P. J. 1996; Scholar, S.R. Kwon S.R. S.G. J. Biol. 1998; 273: Scholar). a number of protein-tyrosine to be activated by H2O2 M. M. T. K. J. Cell Biol. Scholar, Y.S. E. S.G. J. Biol. 1997; Scholar) and of the of have been shown to be involved in cell volume A.L. J. Biol. 2002; 277: Scholar). It be that a intracellular activation by In of in the the and Cl– channel that a role in the activation of these Cl– channels H2O2 of Cl– channels were in a cell we of cells to H2O2 in elicited a Cl– to the Cl– and also to the Cl– described cells also used cells to the of the NAD(P)H oxidase in VSOR Cl– channel activation. is a of the NAD(P)H oxidase, of H2O2 production and of the Cl– by this be with this we used cells with a of the of the NAD(P)H oxidase J. J. 1995; Scholar). is to to the in a of enzyme activity. Cl– was elicited by exogenously H2O2 in the of a In cells with or with the Cl– with and cells that NAD(P)H oxidase is the Cl– oxidase is H2O2 activation of volume-sensitive channels. cells elicited by the used in and of Cl– in a the described in in and cells to activated Cl– in cells and a the described in the to in and cells to a the the of by NAD(P)H H2O2 production by a also in the activation of a Cl– growth is known to a H2O2 response in various cell Y.S. E. S.G. J. Biol. 1997; Scholar) and to the Cl– in cells Y. J. Physiol. (Lond.). Scholar). of cells to in activated an outwardly rectifying Cl– to the Cl– was by intracellular and by A and Cl– was in cells the that of the to its production, as a common VSOR Cl– Furthermore, the Cl– channel activation elicited by was in cells the growth activation of volume-sensitive channels is by NAD(P)H elicited by the used in under conditions and of to of Cl– in and in the or of intracellular were the of was as described Cl– in a the described in in and cells to the as shown in the we have shown that H2O2 is of the that VSOR Cl– channel that H2O2 is an messenger the activation of VSOR Cl– channels in and Furthermore, we have that NAD(P)H oxidase is a in this process by this as a of O2·¯ the production of H2O2 that H2O2 is its by the intracellular an Although the first to activation of NAD(P)H oxidase and the of VSOR Cl– channel activation to be to the role of VSOR Cl– channels in fundamental physiological including cell proliferation and of and in cell in a Volume-activated Cl– channels have been widely studied in their role as regulators of normal cell volume (for review, see Refs. 1Hoffmann E.K. Simonsen L.O. Physiol. Rev. 1989; 69: 315-382Google Scholar and 2Strange K. Jackson P.S. Kidney Int. 1995; 48: 994-1003Google Scholar). However, these channels are increasingly found to be involved in other physiological processes, including cell proliferation. (3Shen M.R. Droogmans G. Eggermont J. Voets T. Ellory J.C. Nilius B. J. Physiol. (Lond.). 2000; 529: 385-394Google Scholar) and apoptosis (4Szabo I. Lepple-Wienhues A. Kaba K.N. Zoratti M. Gulbins E. Lang F. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6169-6174Google Scholar). In general, cells produce O2·¯ that is rapidly converted into H2O2 and its generation is modulated by activation of cell surface receptors, stress responses, and apoptosis (5Rhee S.G. Bae Y.S. Lee S.R. Kwon J. Science's STKE. 2000; http://stke.sciencemag.org/cgi/content/full/sigtrans;2000/53/pe1Google Scholar, 6Johnson T.M. Yu Z.X. Ferrans V.J. Lowenstein R.A. Finkel T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 11848-11852Google Scholar). A fundamental enzyme involved in this process is NAD(P)H oxidase, which was first described in neutrophils. A number of NAD(P)H oxidases-related enzymes were later identified in nonphagocytic cells and some of them are associated to H2O2 production in response to ligands and peptide growth factors (7Lambeth J.D. Curr. Opin. Hematol. 2002; 9: 11-17Google Scholar). Although H2O2 is also known to be produced by xanthine oxidase, NO synthase, and cytochrome P450, as well as the mitochondria, there is no compelling evidence linking them to cell surface receptor activation. It is well documented that addition of exogenous H2O2 or increased intracellular generation of H2O2 influences the function of various proteins, including protein-tyrosine phosphatases, protein kinases, and transcription factors, suggesting that H2O2 might be an intracellular messenger (8Finkel T. Curr. Opin. Cell Biol. 1998; 10: 248-253Google Scholar, 9Suzuki Y.J. Ford G.D. J. Mol. Cell Cardiol. 1999; 31: 345-353Google Scholar, 10Rhee S.G. Exp. Mol. Med. 1999; 31: 53-59Google Scholar). activate VSOR 1The abbreviations used are: VSOR, volume-sensitive outwardly rectifying; DPI, diphenylene iodonium chloride; Tiron, 4,5-dihydroxy-1,3-benzene disulfonic acid; PTP, protein-tyrosine phosphatase; PTK, protein-tyrosine kinase; DTT, dithiothreitol; EGF, epidermal growth factor. 1The abbreviations used are: VSOR, volume-sensitive outwardly rectifying; DPI, diphenylene iodonium chloride; Tiron, 4,5-dihydroxy-1,3-benzene disulfonic acid; PTP, protein-tyrosine phosphatase; PTK, protein-tyrosine kinase; DTT, dithiothreitol; EGF, epidermal growth factor. Cl– channels in response to an increase in cell volume (11Hoffmann E.K. Lambert I.H. Simonsen L.O. Renal Physiol. Biochem. 1988; 11: 221-247Google Scholar, 12Okada Y. Am. J. Physiol. 1997; 273: C755-C789Google Scholar, 13Stutzin A. Torres R. Oporto M. Pacheco P. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1999; 277: C392-C402Google Scholar). These channels are also found to be activated under conditions in which cell volume is constant (14Doroshenko P. Penner R. Neher E. J. Physiol. (Lond.). 1991; 436: 711-724Google Scholar, 15Schumacher P.A. Sakellaropoulos G. Phipps D.J. Schlichter L.C. J. Biol. 1995; Scholar, T. Droogmans G. Nilius B. J. Physiol. (Lond.). 1996; evidence their in a variety of other cell volume VSOR Cl– channel is modulated cell S. J. P. B. Am. J. Physiol. 2002; and proliferation in cells is by these channels R. M. J. Physiol. (Lond.). Scholar). channels are also to a role in of have been shown to activation of outwardly rectifying Cl– channels (4Szabo I. Lepple-Wienhues A. Kaba K.N. Zoratti M. Gulbins E. Lang F. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6169-6174Google which were also activated by swelling A. I. T. Kaba Gulbins E. Lang F. J. Cell Biol. 1998; Scholar). is by of cells volume E. Y. T. A. Y. Proc. Natl. Acad. Sci. U. S. A. 2000; Scholar, Am. J. Physiol. 1996; and of VSOR Cl– channels volume decrease Y. E. Biochem. Physiol. A Mol. Physiol. Scholar). these channels are activated under many we a common that mediates activation of VSOR Cl– channels. In the the question of H2O2 mediates VSOR Cl– channel activation was in cell that H2O2 is a common messenger in VSOR Cl– channel activation in cell volume and cell proliferation. and and cells were as described A. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1997; 273: Scholar). cells were and the of an with and with was with to and with and an of were by In was used of as and was by the the various were the B. of Scholar). in were J. and were were the of R. A. J. Physiol. 1991; Scholar). was and the were was as described A. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1997; 273: of Cell in cell volume were in cells by in of an as described A. Torres R. Oporto M. Pacheco P. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1999; 277: C392-C402Google Scholar, J. 1995; of Cellular H2O2 and and by the cells was by a coupled and as R. Biol. Med. Scholar, E. Science's STKE. and of the J. J. 1995; Scholar) was into the an of the protein to the P. 2000; Scholar). cells were with of the to the were in which and 4,5-dihydroxy-1,3-benzene disulfonic were cells were as described Y. J. M. J. Biol. 2000; Scholar). In the of diphenylene iodonium was of the was by and considered Cell and and cells were as described A. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1997; 273: Scholar). cells were and the of an with and with was with to and with and an of were by In was used of as and was by the the various were the B. of Scholar). in were J. and were were the of R. A. J. Physiol. 1991; Scholar). was and the were was as described A. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1997; 273: Scholar). of Cell in cell volume were in cells by in of an as described A. Torres R. Oporto M. Pacheco P. Eguiguren A.L. Cid L.P. Sepúlveda F.V. Am. J. Physiol. 1999; 277: C392-C402Google Scholar, J. 1995; Scholar). of Cellular H2O2 and and by the cells was by a coupled and as R. Biol. Med. Scholar, E. Science's STKE. Scholar). and of the J. J. 1995; Scholar) was into the an of the protein to the P. 2000; Scholar). cells were with of the to the were Cell in which and 4,5-dihydroxy-1,3-benzene disulfonic were cells were as described Y. J. M. J. Biol. 2000; Scholar). In the of diphenylene iodonium was of the was by and considered VSOR Cl– of cells a cell to H2O2 in activated an outwardly rectifying Cl– with a of the of and was to that elicited by a in to its and Cl– as by the in in anion of the channels activated by H2O2 the Cl– anion and the described VSOR Cl– channels B. Eggermont J. Voets T. G. Droogmans G. Mol. Biol. 1997; Scholar). the of the Cl– was addition of H2O2 with a constant of was H2O2 with an constant to These that addition of H2O2 to cells the activation of a Cl– in the of cell swelling that is the Cl– the of a known VSOR Cl– channel the channels activated by a of the Cl– Furthermore, to a a to the Cl– channels in many cell also Cl– by suggesting that the anion channels activated by H2O2 are the as the channels activated by cell swelling NAD(P)H H2O2 in H2O2 is VSOR Cl– channel be that cells increase intracellular to a increase in intracellular as by a coupled and as an of cell to a a in H2O2 the first by a decrease in H2O2 increase in H2O2 production was the of the and was under or conditions role of NAD(P)H oxidase in the H2O2 generation was In cells with a NAD(P)H oxidase H2O2 production was by that H2O2 a NAD(P)H These are in with the increase in in I.H. J. Biol. Cl– H2O2 increased H2O2 production under conditions activation of the Cl– we the activation of this Cl– H2O2 of cells with the Cl– by the Cl– the that H2O2 is involved in the activation of VSOR Cl– channels. In with these the in cells the NAD(P)H oxidase is an outwardly rectifying Cl– of the Cl– J. Physiol. 2002; Scholar). A of H2O2 generation is the of by the NAD(P)H oxidase to which is or converted to we studied the of the O2·¯ the activation of VSOR Cl– channels. of cells with the Cl– the Cl– that O2·¯ production and to H2O2 are VSOR Cl– channel activation. Cl– channel activation was by H2O2 and by other we in cells by the of the enzyme of H2O2 to cells with the Cl– and that VSOR Cl– channel activation is H2O2 and other of the cells with a elicited a Cl– with properties to that by H2O2 evidence that H2O2 its as a messenger by as that in the found in the of protein-tyrosine Rev. 1998; Scholar, A. A. P. J. 1996; Scholar, S.R. Kwon S.R. S.G. J. Biol. 1998; 273: Scholar). a number of protein-tyrosine to be activated by H2O2 M. M. T. K. J. Cell Biol. Scholar, Y.S. E. S.G. J. Biol. 1997; Scholar) and of the of have been shown to be involved in cell volume A.L. J. Biol. 2002; 277: Scholar). It be that a intracellular activation by In of in the the and Cl– channel that a role in the activation of these Cl– channels H2O2 of Cl– channels were in a cell we of cells to H2O2 in elicited a Cl– to the Cl– and also to the Cl– described cells also used cells to the of the NAD(P)H oxidase in VSOR Cl– channel activation. is a of the NAD(P)H oxidase, of H2O2 production and of the Cl– by this be with this we used cells with a of the of the NAD(P)H oxidase J. J. 1995; Scholar). is to to the in a of enzyme activity. Cl– was elicited by exogenously H2O2 in the of a In cells with or with the Cl– with and cells that NAD(P)H oxidase is the Cl– oxidase is H2O2 activation of volume-sensitive channels. cells elicited by the used in and of Cl– in a the described in in and cells to activated Cl– in cells and a the described in the to in and cells to a the the of by NAD(P)H H2O2 production by a also in the activation of a Cl– growth is known to a H2O2 response in various cell Y.S. E. S.G. J. Biol. 1997; Scholar) and to the Cl– in cells Y. J. Physiol. (Lond.). Scholar). of cells to in activated an outwardly rectifying Cl– to the Cl– was by intracellular and by A and Cl– was in cells the that of the to its production, as a common VSOR Cl– Furthermore, the Cl– channel activation elicited by was in cells the growth activation of volume-sensitive channels is by NAD(P)H elicited by the used in under conditions and of to of Cl– in and in the or of intracellular were the of was as described Cl– in a the described in in and cells to the as shown in the we have shown that H2O2 is of the that VSOR Cl– channel that H2O2 is an messenger the activation of VSOR Cl– channels in and Furthermore, we have that NAD(P)H oxidase is a in this process by this as a of O2·¯ the production of H2O2 that H2O2 is its by the intracellular an Although the first to activation of NAD(P)H oxidase and the of VSOR Cl– channel activation to be to the role of VSOR Cl– channels in fundamental physiological including cell proliferation and of and in cell in a H2O2 VSOR Cl– of cells a cell to H2O2 in activated an outwardly rectifying Cl– with a of the of and was to that elicited by a in to its and Cl– as by the in in anion of the channels activated by H2O2 the Cl– anion and the described VSOR Cl– channels B. Eggermont J. Voets T. G. Droogmans G. Mol. Biol. 1997; Scholar). the of the Cl– was addition of H2O2 with a constant of was H2O2 with an constant to These that addition of H2O2 to cells the activation of a Cl– in the of cell swelling that is the Cl– the of a known VSOR Cl– channel the channels activated by a of the Cl– Furthermore, to a a to the Cl– channels in many cell also Cl– by suggesting that the anion channels activated by H2O2 are the as the channels activated by cell swelling NAD(P)H H2O2 in H2O2 is VSOR Cl– channel be that cells increase intracellular to a increase in intracellular as by a coupled and as an of cell to a a in H2O2 the first by a decrease in H2O2 increase in H2O2 production was the of the and was under or conditions role of NAD(P)H oxidase in the H2O2 generation was In cells with a NAD(P)H oxidase H2O2 production was by that H2O2 a NAD(P)H These are in with the increase in in I.H. J. Biol. Scholar). Cl– H2O2 increased H2O2 production under conditions activation of the Cl– we the activation of this Cl– H2O2 of cells with the Cl– by the Cl– the that H2O2 is involved in the activation of VSOR Cl– channels. In with these the in cells the NAD(P)H oxidase is an outwardly rectifying Cl– of the Cl– J. Physiol. 2002; Scholar). A of H2O2 generation is the of by the NAD(P)H oxidase to which is or converted to we studied the of the O2·¯ the activation of VSOR Cl– channels. of cells with the Cl– the Cl– that O2·¯ production and to H2O2 are VSOR Cl– channel activation. Cl– channel activation was by H2O2 and by other we in cells by the of the enzyme of H2O2 to cells with the Cl– and that VSOR Cl– channel activation is H2O2 and other of the cells with a elicited a Cl– with properties to that by H2O2 evidence that H2O2 its as a messenger by as that in the found in the of protein-tyrosine Rev. 1998; Scholar, A. A. P. J. 1996; Scholar, S.R. Kwon S.R. S.G. J. Biol. 1998; 273: Scholar). a number of protein-tyrosine to be activated by H2O2 M. M. T. K. J. Cell Biol. Scholar, Y.S. E. S.G. J. Biol. 1997; Scholar) and of the of have been shown to be involved in cell volume A.L. J. Biol. 2002; 277: Scholar). It be that a intracellular activation by In of in the the and Cl– channel that a role in the activation of these Cl– channels NAD(P)H H2O2 of Cl– channels were in a cell we of cells to H2O2 in elicited a Cl– to the Cl– and also to the Cl– described cells also used cells to the of the NAD(P)H oxidase in VSOR Cl– channel activation. is a of the NAD(P)H oxidase, of H2O2 production and of the Cl– by this be with this we used cells with a of the of the NAD(P)H oxidase J. J. 1995; Scholar). is to to the in a of enzyme activity. Cl– was elicited by exogenously H2O2 in the of a In cells with or with the Cl– with and cells that NAD(P)H oxidase is the Cl– of by NAD(P)H H2O2 production by a also in the activation of a Cl– growth is known to a H2O2 response in various cell Y.S. E. S.G. J. Biol. 1997; Scholar) and to the Cl– in cells Y. J. Physiol. (Lond.). Scholar). of cells to in activated an outwardly rectifying Cl– to the Cl– was by intracellular and by A and Cl– was in cells the that of the to its production, as a common VSOR Cl– Furthermore, the Cl– channel activation elicited by was in cells the In we have shown that H2O2 is of the that VSOR Cl– channel that H2O2 is an messenger the activation of VSOR Cl– channels in and Furthermore, we have that NAD(P)H oxidase is a in this process by this as a of O2·¯ the production of H2O2 that H2O2 is its by the intracellular an Although the first to activation of NAD(P)H oxidase and the of VSOR Cl– channel activation to be to the role of VSOR Cl– channels in fundamental physiological including cell proliferation and are to B. M. the and to S. the also F. F. and and of the with with

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