Altered Regulation of Airway Epithelial Cell Chloride Channels in Cystic Fibrosis

Frizzell, Raymond A.; Rechkemmer, Gerhard; Shoemaker, R. L.

doi:10.1126/science.2425436

Cited by 536 publications

(215 citation statements)

References 9 publications

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“…In addition, voltage steps which have been found to effectively unblock quiescent outward rectifier chloride channels in patches excised from several epithelia (e.g. [29]) failed to activate low conductance channels under the cell-attached conditions. The properties of the low conductance channels were therefore deduced from the 14 experiments in which channel activity was induced by procedures that increased intracellular CAMP.…”

Section: Resultsmentioning

confidence: 99%

“…In pulmonary tissues, both intracellular Ca" and CAMP have been implicated in Cl-secretion [11,12], and it is assumed that separate Cl-channels are activated by these two regulatory pathways [13]. CF causes a decrease in CAMP-dependent [ 14,151 but not calciumdependent regulation of chloride transport in the airway [14]. Various Cl-channels have been identified in tracheal surface epithelial cells [ 16,171, including CFTRCl-channels in immortalized human airway cell lines [18] but there have been no single channel studies reported for submucosal gland cells, although these cells are believed to be the major site of mucus secretion in the airway epithelium in situ hybridization and immunocytochemistry indicate that CFTR expression is far higher in submucosal glands than in other airway cells [21].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of cAMP dependent CFTR‐chloride channels in human trache gland cells

Becq¹,

Merten²,

Voelckel³

et al. 1993

FEBS Letters

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Human tracheal gland cells are believed to be a major site at the origin of cystic fibrosis. Since this disease is due to mutations in a protein called CFTR, we looked for the activity of CFTR in human tracheal gland cells in culture. We have identified CFTR‐like chloride‐selective channels as having a linear current‐voltage relationship and unitary conductance of 7 pS in these cells. In cell‐attached patches, theophylline (1 mM), IBMX (1 mM), or a cocktail of dibutyryl cAMP (1 mM) and IBMX (0.1 mM) promoted the opening of channels. The unitary current had a reversal potential close to the cell resting potential. Replacement of choline by K+ or Na+ in the pipette solution was without effect on the current‐voltage relationship, the reversal potential or the unitary conductance, which is consistent with the chloride selectivity of the channel. Channels were always found clustered and their opening probability was not noticeably dependent on membrane potential. This work therefore represents the first observation of a CFTR‐like channel activity in submucosal gland cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of cAMP dependent CFTR‐chloride channels in human trache gland cells

Becq¹,

Merten²,

Voelckel³

et al. 1993

FEBS Letters

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“…Defective regulation of this channel in airway epithelia plays a major role in the impaired secretion found in cystic fibrosis (Frizzell et al, 1986;McCann and Welsh, 1990). Another similarity with the anion channel of airway epithelia is the activation by excision and strong depolarization (Frizzell et al, 1986;Welsh, 1986a). The mechanism for this activation is not known (McCann and Welsh, 1990).…”

Section: Currents"mentioning

confidence: 99%

“…These similar characteristics are an outwardly rectifying I-V relation, conductance of near 50 pS at 0 mV with symmetrical 112 mM CI solutions, at least two open and two closed states and an open probability that increases with depolarization. In most cases this anion channel has been found at the apical membranes of secretory epithelia: trachea (Frizzell, Rechkemmer, and Shoemaker, 1986;Welsh, 1986a, b;Welsh and Liedtke, 1986), dogfish rectal gland (Greger, Schlatter, and G6gelein, 1987b), T84 colonic cell line (Halm, Rechkemmer, Schoumacher, and FrizzeU, 1988;Tabcharani et al, 1989), cultured nasal airway (Kunzelmann, Pavest~dt, and Greger, 1989b), pancreatic duct cell lines (Tabcharani et al, 1989;Schoumacher, Ram, Iannuzzi, Bradbury, Wallace, Hon, Kelly, Schmid, Gelder, Rado, and Frizzell, 1990), and sweat glands (Krouse, Hagiwara, Chen, Lewinston, and Wine, 1989;Tabcharani et al, 1989). It has also been observed at the basolateral membrane of the rat thick ascending limb of Henle's loop .…”

Section: Currents"mentioning

confidence: 99%

Whole-cell and single channel K+ and Cl- currents in epithelial cells of frog skin.

1991

The Journal of General Physiology

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A B S T R A C T Whole-cell and single channel currents were studied in cells from frog (R. pipiens and R. catesbiana) skin epithelium, isolated by collagenase and trypsin treatment, and kept in primary cultures up to three days. Whole-cell currents did not exhibit any significant time-dependent kinetics under any ionic conditions used. With an external K gluconate Ringer solution the currents showed slight inward rectification with a reversal potential near zero and an average conductance of 5 nS at reversal. Ionic substitution of the external medium showed that most of the cell conductance was due to K and that very little, if any, Na conductance was present. This confirmed that most cells originate from inner epithelial layers and contain membranes with basolateral properties. At voltages more positive than 20 mV outward currents were larger with K in the medium than with Na or N-methyl-Dglucamine. Such behavior is indicative of a multi-ion transport mechanism. Wholecell K current was inhibited by external Ba and quinidine. Blockade by Ba was strongly voltage dependent, while that by quinidine was not. In the presence of high external CI, a component of outward current that was inhibited by the anion channel blocker diphenylamine-2-carboxylate (DPC) appeared in 70% of the cells. This component was strongly outwardly rectifying and reversed at a potential expected for a C1 current. At the single channel level the event most frequently observed in the cell-attached configuration was a K channel with the following characteristics: inward-rectifying I-V relation with a conductance (with 112.

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“…O utwardly rectifying chloride (Cl − ) channels (ORCC, ICOR, ORDIC) of intermediate single-channel conductance of about 50 pS are expressed abundantly (1)(2)(3). These channels are activated upon excision of the cell membrane from the intact cell and after strong depolarization (1)(2)(3)(4)(5).…”

mentioning

confidence: 99%

Anoctamin 6 is an essential component of the outwardly rectifying chloride channel

Martins

Faria

Kongsuphol

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

145

161

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Outwardly rectifying chloride channels (ORCC, ICOR) of intermediate single-channel conductance of around 50 pS, are ubiquitously expressed, but have remained a mystery since their description more than 25 y ago. These channels have been shown to be activated on membrane excision and depolarization of the membrane voltage and by cAMP in the presence of the cystic fibrosis transmembrane conductance regulator. We show that anoctamin 6 (Ano6), a member of the recently identified family of putative Cl − channels, is the crucial component of ORCC single-channel and whole-cell currents in airway epithelial cells and Jurkat T lymphocytes. Cystic fibrosis transmembrane conductance regulator augmented ORCC produced by Ano6 in A549 airway epithelial cells. Ano6 is activated during membrane depolarization or apoptosis of Jurkat T lymphocytes and epithelial cells, and is inhibited by 5-nitro-2-(3-phenylpropylamino) benzoic acid, 4,4′-diisothio-cyanostilbene-2,2′-disulfonic acid, or AO1. Ano6 belongs to the basic equipment of any cell type, including colonic surface epithelial cells. It forms the essential component of ORCC and seems to have a role for cell shrinkage and programmed cell death.

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Altered Regulation of Airway Epithelial Cell Chloride Channels in Cystic Fibrosis

Cited by 536 publications

References 9 publications

Characterization of cAMP dependent CFTR‐chloride channels in human trache gland cells

Characterization of cAMP dependent CFTR‐chloride channels in human trache gland cells

Whole-cell and single channel K+ and Cl- currents in epithelial cells of frog skin.

Anoctamin 6 is an essential component of the outwardly rectifying chloride channel

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