Chloride and potassium channels in cystic fibrosis airway epithelia

Abstract

Cystic fibrosis, the most common lethal genetic disease in Caucasians, is characterized by a decreased permeability in sweat gland duct and airway epithelia. In sweat duct epithelium, a decreased Cl- permeability accounts for the abnormally increased salt content of sweat. In airway epithelia a decreased Cl- permeability, and possibly increased sodium absorption, may account for the abnormal respiratory tract fluid. The Cl- impermeability has been localized to the apical membrane of cystic fibrosis airway epithelial cells. The finding that hormonally regulated Cl- channels make the apical membrane Cl- permeable in normal airway epithelial cells suggested abnormal Cl- channel function in cystic fibrosis. Here we report that excised, cell-free patches of membrane from cystic fibrosis epithelial cells contain Cl- channels that have the same conductive properties as Cl- channels from normal cells. However, Cl- channels from cystic fibrosis cells did not open when they were attached to the cell. These findings suggest defective regulation of Cl- channels in cystic fibrosis epithelia; to begin to address this issue, we performed two studies. First, we found that isoprenaline, which stimulates Cl- secretion, increases cellular levels of cyclic AMP in a similar manner in cystic fibrosis and non-cystic fibrosis epithelial cells. Second, we show that adrenergic agonists open calcium-activated potassium channels, indirectly suggesting that calcium-dependent stimulus-response coupling is intact in cystic fibrosis. These data suggest defective regulation of Cl- channels at a site distal to cAMP accumulation.

Concomitant activation of Cl‐ and K+ currents by secretory stimulation in human epithelial cells.

“…In cystic fibrosis secretory cells, the K+ permeability of the epithelium is not altered (Welsh & Liedtke, 1986;Kunzelmann et al 1989;Goldstein, Shapiro, Rao & Layden, 1991). It is hypothesized that the activation of K+ channel activity may be sufficient per se to amplify the background Cl-secretion, whatever the underlying Clchannel class and its activation mode.…”

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

“…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 .…”

Potentiation of Disease-associated Cystic Fibrosis Transmembrane Conductance Regulator Mutants by Hydrolyzable ATP Analogs

“…CF is characterized by the absence of cAMP-stimulated Cl Ϫ current across a variety of epithelia, including the nasal epithelium (7), airway epithelia (8), pancreatic ducts (9), sweat glands (10), and the intestine (6). More than 1500 disease-associated mutations have been identified, and they can be grouped into at least four classes according to the different mechanisms by which they cause channel dysfunction: defective protein production, defective protein processing (for example ⌬F508), defective activation and regulation (⌬F508, G551D), and defective conductance.…”