Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl- channel function

Reddy, M. M.; Light, Michael J.; Quinton, Paul M.

doi:10.1038/46297

Cited by 216 publications

(165 citation statements)

References 25 publications

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“…ENaC hyperactivity results in hyperpolarization of airway epithelia, as is evidenced by increases in the change in the transepithelial potential of the nasal airway in response to amiloride (41). In contrast, activation of CFTR in sweat ducts leads to an enhancement in ENaC activity, suggesting that regulatory interactions between CFTR and ENaC may be tissue-specific (9).…”

Section: Cftr Is a CLmentioning

confidence: 90%

“…Functional interactions between CFTR and ENaC have been observed in both epithelial and non-epithelial cells (2)(3)(4)(5)(6)(7)(8). The activation of CFTR is generally associated with an inhibition of ENaC, although activation of CFTR leads to activation of ENaC in the sweat duct (9), suggesting that the regulatory interactions between these two transporters are complex. The co-expression of CFTR and ENaC in Xenopus oocytes results in a decrease in ENaC-mediated Na ϩ transport in the presence of activated CFTR (4 -7), a regulatory interaction that mimics CFTR/ENaC interactions in the airway.…”

mentioning

confidence: 99%

“…In addition to functioning as a cAMPactivated, ATP-dependent Cl Ϫ channel, CFTR influences the transepithelial transport of other solutes, including Na ϩ via the epithelial sodium channel (ENaC), Cl Ϫ via an outwardly rectifying Cl Ϫ channel, HCO3 Ϫ , glutathione, and ATP (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Functional interactions between CFTR and ENaC have been observed in both epithelial and non-epithelial cells (2)(3)(4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

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Genistein Restores Functional Interactions between ΔF508-CFTR and ENaC in Xenopus Oocytes

Suaud¹,

Li²,

Jiang³

et al. 2002

Journal of Biological Chemistry

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The cystic fibrosis transmembrane conductance regulator (CFTR), in addition to its Cl ؊ channel properties, has regulatory interactions with other epithelial ion channels including the epithelial Na ؉ channel (ENaC). Both the open probability and surface expression of wild type CFTR Cl ؊ channels are increased significantly when CFTR is co-expressed in Xenopus oocytes with ␣␤␥-ENaC, and conversely, the activity of ENaC is inhibited following wild type CFTR activation. Using the Xenopus oocyte expression system, a lack of functional regulatory interactions between ⌬F508-CFTR and ENaC was observed following activation of ⌬F508-CFTR by forskolin and isobutylmethylxanthine (IBMX). Whole cell currents in oocytes expressing ENaC alone decreased in response to genistein but increased in response to a combination of forskolin and IBMX followed by genistein. In contrast, ENaC currents in oocytes coexpressing ENaC and ⌬F508-CFTR remained stable following stimulation with forskolin/IBMX/genistein. Furthermore, co-expression of ⌬F508-CFTR with ENaC enhanced the forskolin/IBMX/genistein-mediated activation of ⌬F508-CFTR. Our data suggest that genistein restores regulatory interactions between ⌬F508-CFTR and ENaC and that combinations of protein repair agents, such as 4-phenylbutyrate and genistein, may be necessary to restore ⌬F508-CFTR function in vivo.

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Section: Cftr Is a CLmentioning

confidence: 90%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Genistein Restores Functional Interactions between ΔF508-CFTR and ENaC in Xenopus Oocytes

Suaud¹,

Li²,

Jiang³

et al. 2002

Journal of Biological Chemistry

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“…It is caused by mutations in a 230-kb gene located on chromosome seven that codes for CFTR (1). CFTR functions in the main as a cAMP-regulated chloride channel but also regulates the activity of other ion channels and transporters such as apical Enac, basolateral Na/K ATPase (2,3), and the outwardly rectifying chloride channel (4), and can transport bicarbonate (5). Progression of lung disease due to chronic infection is the main cause of morbidity and mortality in CF (6).…”

Section: Cystic Fibrosis (Cf)mentioning

confidence: 99%

Interleukin-1β Differentially Regulates β2 Adrenoreceptor and Prostaglandin E2-mediated cAMP Accumulation and Chloride Efflux from Calu-3 Bronchial Epithelial Cells

Clayton

Holland

Pang

et al. 2005

Journal of Biological Chemistry

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Here we tested the effect of interleukin-1␤, a proinflammatory cytokine, on cAMP accumulation and chloride efflux in Calu-3 airway epithelial cells in response to ligands binding to adenylyl cyclase-coupled receptors such as the ␤ 2 adrenoreceptor and EP prostanoid receptors. Interleukin-1␤ significantly increased isoprenaline-induced cAMP accumulation by increasing ␤ 2 adrenoreceptor numbers via a protein kinase A-dependent mechanism. In contrast, interleukin-1␤ significantly impaired prostaglandin E 2 -induced cAMP accumulation by induction of cyclo-oxygenase-2, prostaglandin E 2 production, and a resulting downregulation of adenylyl cyclase. The cAMP changes were all mirrored by alterations in chloride efflux assessed using the fluorescent chloride probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide with interleukin-1␤ increasing chloride efflux in response to isoprenaline and reducing the response to prostaglandin E 2 . Studies with glibenclamide confirmed that chloride efflux was via the cystic fibrosis transmembrane conductance regulator. Calu-3 expresses EP 4 receptors, but not EP 2 , and receptor expression is reduced by interleukin-1␤. Collectively, these results provide mechanistic insight into how interleukin-1␤ can differentially regulate cAMP generation and chloride efflux in response to different adenylyl cyclase-coupled ligands in the same cell. These findings have important implications for diseases involving inflammation and abnormal ion flux such as cystic fibrosis.

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“…Sweat duct cells, however, are an exception since in these CFTR activity promotes ENaC activation, prerequisite for the reabsorption of sodium and chloride that results in a hypotonic sweat and retention of salt in the body during sweating. 29 Loss of this synergy is the cause of the hypertonic sweat characteristic of CF patients. The uneven interaction between CFTR and ENaC activities is particularly relevant in the lung of CF patients because the unbalance between CFTR-mediated Cl ¡ secretion and ENaC-mediated Na C reabsorption dysregulates the net amount of salt and water in the airway surface liquid (ASL), and thereby causes the thickening of airway secretions and impairs the clearance of bacteria and other contaminants from the lungs.…”

Section: Regulation Of Enac Density At the Cell Surface By Rab Gtpasesmentioning

confidence: 99%

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

Farinha

Matos

2017

Small GTPases

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The amount of ion channels and transporters present at the plasma membrane is a crucial component of the overall regulation of ion transport. The number of channels present result from an intricate network of proteins that controls the late events of channel trafficking, such as endocytosis, recycling and targeting to lysosomal degradation. Small GTPases of the Rab family are key players in these processes thus contributing to regulation of fluid secretion and ion homeostasis. In epithelia, this involves mainly the balance between the chloride channel CFTR and the sodium channel ENaC, whose misfunction is a hallmark of cystic fibrosis -the commonest recessive disorder in Caucasians. Here, we review the role of GTPases in regulating trafficking of ion channels and transporters, comparing what is known for CFTR and ENaC with other types of channels. We also discuss how feasible would be to target the Rab machinery to handle a disorder such as CF. Trafficking and Rab proteinsRegulation of ion and solute transport at the membrane of cells depends on the balance between the function of each channel or transporter and on the number of molecules present. 1 The latter is regulated by the protein trafficking machinery, which controls the process through which a membrane protein is delivered from its place of synthesis -the membrane of the endoplasmic reticulum -to its final destination -the plasma membrane (PM). Besides these anterograde trafficking pathways, channels and transporters also undergo endocytosis followed by either recycling to the PM or targeting to the lysosomal compartment. These late trafficking events are controlled by several protein partners, that include protein kinases, myosins and small GTPases, among which Rab proteins. 1 Rab GTPases form the biggest subfamily of the Ras superfamily of small GTPases. As most members of this superfamily, they function as molecular switches alternating between 2 conformational status -a GTP-bound active form and a GDP-bound inactive form. 2,3 The human subfamily contains more than 60 members that reversibly associate with different intracellular membranes, due to their post-translational modification with geranylgeranyl groups. 4 This association with membranes promotes interactions with other components of the trafficking machinery, such as coat components, motor proteins and SNAREs. 2 These characteristics make them relevant players in the control of membrane identity, in vesicle formation, motility and function, regulating the trafficking of many different classes of proteins, among which channels and transporters. 5

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Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl- channel function

Cited by 216 publications

References 25 publications

Genistein Restores Functional Interactions between ΔF508-CFTR and ENaC in Xenopus Oocytes

Genistein Restores Functional Interactions between ΔF508-CFTR and ENaC in Xenopus Oocytes

Interleukin-1β Differentially Regulates β2 Adrenoreceptor and Prostaglandin E2-mediated cAMP Accumulation and Chloride Efflux from Calu-3 Bronchial Epithelial Cells

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

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