In vivo evidence of altered chloride but not potassium secretion in cystic fibrosis rectal mucosa

Goldstein, Jay L.; Shapiro, Alan; Rao, Mrinalini C.; Layden, Thomas J.

doi:10.1016/0016-5085(91)90728-4

Cited by 31 publications

(18 citation statements)

References 22 publications

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“…The cAMPstimulated current was inhibited by the serosal addition of bumetanide, which inhibits C1-entry into the cell at the basolateral membrane, confirming that the change was due to Cl -secretion. The lack of cAMP-stimulated Cl -secretion in AF/AF intestine is consistent with abnormalities reported in humans (34)(35)(36) and null mice (9)(10)(11)(12)37). CFTR plays a central role in pancreatic duct secretion, and loss of function causes pancreatic insufficiency in patients with CF (2,38).…”

Section: Methodssupporting

confidence: 80%

A mouse model for the delta F508 allele of cystic fibrosis.

et al. 1995

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The most common cause of cystic fibrosis is a mutation that deletes phenylalanine 508 in cystic fibrosis transmembrane conductance regulator (CFTR). The AF508 protein is misprocessed and degraded rather than traveling to the apical membrane. We used a novel strategy to introduce the AF508 mutation into the mouse CFTR gene. Affected epithelia from homozygous AF508 mice lacked CFTR in the apical membrane and were Cl -impermeable. These abnormalities are the same as those observed in patients with AF508 and suggest that these mice have the same cellular defect. 40% of homozygous AF508 animals survived into adulthood and displayed several abnormalities found in human disease and in CFTR null mice. These animals should provide an excellent model to investigate pathogenesis and to examine therapies directed at correcting the AF508 defect. (J. Clin.

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Section: Methodssupporting

confidence: 80%

A mouse model for the delta F508 allele of cystic fibrosis.

et al. 1995

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“…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.…”

Section: Two Types Of K+ Currents In the T84 Cell Linementioning

confidence: 99%

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

Baró

Roch

Hongre

et al. 1994

The Journal of Physiology

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1. Whole-cell currents were investigated in the model salt-secreting epithelium, human T84 cell line, by means of the perforated patch-clamp technique. In the control extracellular medium containing Cl-, depolarizing voltage ramps evoked current responses which peaked at 5A43 + 0-81 pA pF-' at +60 mV and had a reversal potential (Erev) of -38-4 + 2-5 mV (n = 23).2. Activation of the cAMP pathway with forskolin increased the current at +60 mV from (n =6) and from 6-36 to 34-13 pA pF' (n = 4), respectively. With both agonists, Erev was shifted either towards the reversal potential for potassium, EK, or towards the reversal potential for chloride, Ecl, depending on the cell.4. In the absence of chloride ions (gluconate substituted), stimulation of the Ca2+ pathway activated a time-independent outward current of large amplitude. This current exhibited inward rectification at positive voltages, reverted at -89-5 + 0-2 mV and was markedly reduced by charybdotoxin (10 nM), a specific blocker of Ca2+-activated K+ channels. When a voltage step protocol was used, increased [Ca2+]i also activated an outward current at potentials more positive than -40 mV which slowly relaxed during depolarizing steps. 5. The activation of both (i) a time-independent inwardly rectifying charybdotoxinsensitive K+ current, and (ii) a time-dependent slowly inactivating current was also produced by cAMP stimulation. 6. We concluded that (i) in the T84 epithelial cells, both Cl-and K+ currents are concomitantly increased by secretagogue stimulation, and (ii) two different types of K+ conductances are activated by either the cAMP or the intracellular Ca21 secreting pathways.

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“…Telephone: (607) 253-3708. E-mail: bup1@cornell.edu. unaffected individuals, but is significantly reduced or absent from CFTR-defective intestinal epithelia (Berschneider et al, 1988;Taylor et al, 1988;Willumsen and Boucher, 1989;Goldstein et al, 1991;Hardcastle et al, 1991;Smith et al, 1995). However, little is known about the molecular basis of these channels.…”

Section: Introductionmentioning

confidence: 96%