Second‐messenger regulation of sodium transport in mammalian airway epithelia.

Graham, Alexander; Steel, D. M.; Alton, Eric W.F.W.; Geddes, Duncan M.

doi:10.1113/jphysiol.1992.sp019240

Cited by 24 publications

(17 citation statements)

References 40 publications

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“…A variety of studies have been conducted in freshly isolated tissues, primary cultures, and cell lines from multiple species, but there is not a consensus as to the mechanism(s) responsible for inhibition of sodium transport. Most of the results support a role for calcium mobilization (13,21), but not PKC activation, despite evidence that direct activation of PKC with phorbol esters can lead to inhibition of amiloride-sensitive sodium absorption in airways (18,25). O'Grady and coworkers (30) recently reported that extracellular UTP elicited a transient stimulation of Cl secretion, followed by a sustained inhibition of amiloride-sensitive sodium absorption in cultured porcine endometrial epithelial cells.…”

Section: Discussionmentioning

confidence: 98%

“…Several receptor agonists cause acute and/or chronic downregulation of Na ϩ absorption, including epidermal growth factor (EGF) (10,32,43,46), acetylcholine and PGE 2 (6,15,17,46), and extracellular ATP (26). Several intracellular signaling pathways (i.e., PKC, calcium, Src kinase, ERK1/2) have been implicated (17,18,21,24,43,47); however, the precise molecular mechanisms responsible for inhibition of ENaC function have not been fully elucidated.ENaC belongs to the degenerin/ENaC gene superfamily, and functional channels are thought to be composed of some combination of three homologous subunits: ␣-, ␤-, and ␥-ENaC (7). Each subunit has the predicted membrane topology of two hydrophobic membrane-spanning regions, a highly conserved large extracellular cysteine-rich loop, and intracellular NH 2 and COOH termini.…”

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confidence: 99%

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A role for ERK1/2 in EGF- and ATP-dependent regulation of amiloride-sensitive sodium absorption

Falin

Veizis

Cotton

2005

American Journal of Physiology-Cell Physiology

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-Receptor-mediated inhibition of amiloride-sensitive sodium absorption was observed in primary and immortalized murine renal collecting duct cell (mCT12) monolayers. The addition of epidermal growth factor (EGF) to the basolateral bathing solution of polarized monolayers reduced amiloride-sensitive short-circuit current (I sc) by 15-25%, whereas the addition of ATP to the apical bathing solution decreased Isc by 40 -60%. Direct activation of PKC with phorbol 12-myristate 13-acetate (PMA) and mobilization of intracellular calcium with 2,5-di-tert-butyl-hydroquinone (DBHQ) reduced amiloride-sensitive I sc in mCT12 monolayers by 46 Ϯ 4% (n ϭ 8) and 22 Ϯ 2% (n ϭ 8), respectively. Exposure of mCT12 cells to EGF, ATP, PMA, and DBHQ caused an increase in phosphorylation of p42/p44 (extracellular signal-regulated kinase; ERK1/2). Pretreatment of mCT12 monolayers with an ERK kinase inhibitor (PD-98059; 30 M) prevented phosphorylation of p42/p44 and significantly reduced EGF, ATP, and PMA-induced inhibition of amiloride-sensitive I sc. In contrast, pretreatment of monolayers with a PKC inhibitor (bisindolylmaleimide I; GF109203x; 1 M) almost completely blocked the PMA-induced decrease in I sc, but did not alter the EGF-or ATP-induced inhibition of Isc. The DBHQ-mediated decrease in I sc was due to inhibition of basolateral Na ϩ -K ϩ -ATPase, but EGF-, ATP-, and PMA-induced inhibition was most likely due to reduced apical sodium entry (epithelial Na ϩ channel activity). The results of these studies demonstrate that acute inhibition of amiloride-sensitive sodium transport by extracelluar ATP and EGF involves ERK1/2 activation and suggests a role for MAP kinase signaling as a negative regulator of electrogenic sodium absorption in epithelia.mitogen-activated protein kinase; epithelial ion transport; epithelial sodium channel AMILORIDE-SENSITIVE Na ϩ transport, mediated by the epithelial Na ϩ channel (ENaC), is an important pathway for Na ϩ absorption by the colon and for Na ϩ retention by the distal nephron (16). A similar mechanism for Na ϩ transport is in the salivary duct, urinary bladder, sweat duct, and airway epithelium, where the process is responsible for the clearance of fetal lung liquid at birth (9, 28) and for control of the composition and/or depth of airway surface liquid in the postnatal lung (4). Defective regulation of ENaC and resultant Na ϩ hyperabsorption by the airway surface epithelium is thought to be an important component of the pathophysiology of cystic fibrosis (5). ENaC loss-of-function mutations (e.g., pseudohypoaldosteronism type I) are known to cause hyponatremia, hyperkalemia, and salt wasting, whereas gain-of-function mutations (e.g., salt-sensitive hypertension, Liddle's syndrome) lead to an increase in ENaC activity and excess Na ϩ reabsorption (20, 31).Corticosteroids, insulin, and vasopressin cause acute and/or chronic stimulation of sodium transport in epithelial cells (45) by several mechanisms, including alterations in ENaC open probability (23), increased synthesis of channel subunits...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

A role for ERK1/2 in EGF- and ATP-dependent regulation of amiloride-sensitive sodium absorption

Falin

Veizis

Cotton

2005

American Journal of Physiology-Cell Physiology

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“…It might contribute to the increased Na ϩ absorption described in CF airway epithelia (45). Na ϩ absorption is reduced by stimuli causing cytosolic Ca 2ϩ increases (46,47). Therefore, a defective TRPV4 channel might result in a reduced mechanically induced Ca 2ϩ signal and increased amiloride-sensitive Na ϩ absorption.…”

Section: Discussionmentioning

confidence: 99%

Swelling-activated Ca2+ Entry via TRPV4 Channel Is Defective in Cystic Fibrosis Airway Epithelia

Arniges

Vázquez

Fernández-Fernández

et al. 2004

Journal of Biological Chemistry

168

128

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The vertebrate transient receptor potential cationic channel TRPV4 has been proposed as an osmo-and mechanosensor channel. Studies using knock-out animal models have further emphasized the relevance of the TRPV4 channel in the maintenance of the internal osmotic equilibrium and mechanosensation. However, at the cellular level, there is still one important question to answer: does the TRPV4 channel generate the Ca 2؉ signal in those cells undergoing a Ca 2؉ -dependent regulatory volume decrease (RVD) response? RVD in human airway epithelia requires the generation of a Ca 2؉ signal to activate Ca 2؉ -dependent K ؉ channels. The RVD response is lost in airway epithelia affected with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator channel. We have previously shown that the defective RVD in CF epithelia is linked to the lack of swelling-dependent activation of Ca 2؉ -dependent K ؉ channels. In the present study, we show the expression of TRPV4 in normal human airway epithelia, where it functions as the Ca 2؉ entry pathway that triggers the RVD response after hypotonic stress, as demonstrated by TRPV4 antisense experiments. However, cell swelling failed to trigger Ca 2؉ entry via TRPV4 channels in CF airway epithelia, although the channel's response to a specific synthetic activator, 4␣-phorbol 12,13-didecanoate, was maintained. Furthermore, RVD was recovered in CF airway epithelia treated with 4␣-phorbol 12,13-didecanoate. Together, these results suggest that defective RVD in CF airway epithelia might be caused by the absence of a TRPV4-mediated Ca 2؉ signal and the subsequent activation of Ca 2؉ -dependent K ؉ channels.

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“…An autocrine regulation of [Ca 2+ ] i by CFTR activation could stimulate Ca 2+ -activated Cl − current (Mason, Paradiso & Boucher, 1991;Urbach et al, 1994;Schwiebert et al, 1995). In addition, amiloridesensitive sodium absorption through epithelia has been shown to be indirectly inhibited by experimental manoeuvres designed to increase [Ca 2+ ] i (Graham et al, 1992;Ismailov, Berdiev & Benos, 1995;Harvey, 1995;Maguire et al, 1999). Therefore, the CFTR protein activation could control the balance between secretion and absorption by simultaneous stimulation of chloride secretion through other Cl − channels while downregulating sodium absorption in normal epithelia.…”

Section: Discussionmentioning

confidence: 97%

Regulation of Intracellular Ca 2+ by CFTR in Chinese Hamster Ovary Cells

Urbach

Harvey

1999

Journal of Membrane Biology

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In cystic fibrosis, the mutation of the CFTR protein causes reduced transepithelial Cl(-) secretion. As recently proposed, beside its role of Cl(-) channel, CFTR may regulate the activity of other channels such as a Ca(2+)-activated Cl(-) channel. Using a calcium imaging system, we show, in adenovirus-CFTR infected Chinese Hamster Ovary (CHO) cell monolayers, that CFTR can act as a regulator of intracellular [Ca(2+)](i) ([Ca(2+)](i)), involving purino-receptors. Apical exposure to ATP or UTP produced an increase in ([Ca(2+)](i) in noninfected CHO cell monolayers (CHO-WT), in CHO monolayers infected with an adenovirus-CFTR (CHO-CFTR) or infected with an adenovirus-LacZ (CHO-LacZ). The transient [Ca(2+)](i) increase produced by ATP or UTP could be mimicked by activation of CFTR with forskolin (20 microm) in CHO-CFTR confluent monolayers. However, forskolin had no significant effect on [Ca(2+)](i) in noninfected CHO-WT or in CHO-LacZ cells. Pretreatment with purino-receptor antagonists such as suramin (100 microm) or reactive blue-2. (100 microm), and with hexokinase (0.28 U/mg) inhibited the [Ca(2+)](i) response to forskolin in CHO-CFTR infected cells. Taken together, our experiments provide evidence for purino-receptor activation by ATP released from the cell and regulation of [Ca(2+)](i) by CFTR in CHO epithelial cell membranes.

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Second‐messenger regulation of sodium transport in mammalian airway epithelia.

Cited by 24 publications

References 40 publications

A role for ERK1/2 in EGF- and ATP-dependent regulation of amiloride-sensitive sodium absorption

A role for ERK1/2 in EGF- and ATP-dependent regulation of amiloride-sensitive sodium absorption

Swelling-activated Ca2+ Entry via TRPV4 Channel Is Defective in Cystic Fibrosis Airway Epithelia

Regulation of Intracellular Ca 2+ by CFTR in Chinese Hamster Ovary Cells

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