Where have all the Na+ channels gone? In search of functional ENaC in exocrine pancreas

Novak, Ivana; Hansen, Mette R

doi:10.1016/s0005-2736(02)00598-9

Cited by 20 publications

(18 citation statements)

References 34 publications

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“…Low fluid volume in the amniotic sac may suggest Na ϩ and water hyperabsorption. Similarly, Na ϩ hyperabsorption in gastrointestinal (GI) tissues such as pancreas and liver may hamper optimal secretion of anions such as HCO 3 Ϫ and Cl Ϫ that water follows (2,36,44). Such an impairment of secretion due to the counteractive movement of Na ϩ absorption (which is normally less prominent in these two particular GI tissues) could be detrimental.…”

Section: Discussionmentioning

confidence: 99%

Heightened epithelial Na⁺ channel-mediated Na⁺ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia

Olteanu¹,

Yoder²,

Liu³

et al. 2006

American Journal of Physiology-Cell Physiology

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The Tg737 degrees (rpk) autosomal recessive polycystic kidney disease (ARPKD) mouse carries a hypomorphic mutation in the Tg737 gene. Because of the absence of its protein product Polaris, the nonmotile primary monocilium central to the luminal membrane of ductal epithelia, such as the cortical collecting duct (CCD) principal cell (PC), is malformed. Although the functions of the renal monocilium remain elusive, primary monocilia or flagella on neurons act as sensory organelles. Thus we hypothesized that the PC monocilium functions as a cellular sensor. To test this hypothesis, we assessed the contribution of Polaris and cilium structure and function to renal epithelial ion transport electrophysiology. Properties of Tg737 degrees (rpk) mutant CCD PC clones were compared with clones genetically rescued with wild-type Tg737 cDNA. All cells were grown as polarized cell monolayers with similarly high transepithelial resistance on permeable filter supports. Three- to fourfold elevated transepithelial voltage (V(te)) and short-circuit current (I(sc)) were measured in mutant orpk monolayers vs. rescued controls. Pharmacological and cell biological examination of this enhanced electrical end point in mutant monolayers revealed that epithelial Na(+) channels (ENaCs) were upregulated. Amiloride, ENaC-selective amiloride analogs (benzamil and phenamil), and protease inhibitors (aprotinin and leupeptin) attenuated heightened V(te) and I(sc). Higher concentrations of additional amiloride analogs (ethylisopropylamiloride and dimethylamiloride) also revealed inhibition of V(te). Cell culture requirements and manipulations were also consistent with heightened ENaC expression and function. Together, these data suggest that ENaC expression and/or function are upregulated in the luminal membrane of mutant, cilium-deficient orpk CCD PC monolayers vs. cilium-competent controls. When the genetic lesion causes loss or malformation of the monocilium, ENaC-driven Na(+) hyperabsorption may explain the rapid emergence of severe hypertension in a majority of patients with ARPKD.

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Section: Discussionmentioning

confidence: 99%

Heightened epithelial Na⁺ channel-mediated Na⁺ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia

Olteanu¹,

Yoder²,

Liu³

et al. 2006

American Journal of Physiology-Cell Physiology

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“…The site of expression of ␦-ENaC in the human pancreas is unknown. To date, no amiloride-sensitive Na ϩ conductance has been detected in pancreatic duct cells of different species (24,64,102). It remains to be seen whether ␦-ENaC is expressed in the endocrine pancreas, where it may play a role in controlling cell excitability.…”

Section: F334mentioning

confidence: 99%

The epithelial sodium channel δ-subunit: new notes for an old song

Giráldez¹,

Rojas

Jou

et al. 2012

American Journal of Physiology-Renal Physiology

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Amiloride-sensitive epithelial Na(+) channels (ENaCs) can be formed by different combinations of four homologous subunits, named α, β, γ, and δ. In addition to providing an apical entry pathway for transepithelial Na(+) reabsorption in tight epithelia such as the kidney distal tubule and collecting duct, ENaCs are also expressed in nonepithelial cells, where they may play different functional roles. The δ-subunit of ENaC was originally identified in humans and is able to form amiloride-sensitive Na(+) channels alone or in combination with β and γ, generally resembling the canonical kidney ENaC formed by α, β, and γ. However, δ differs from α in its tissue distribution and channel properties. Despite the low sequence conservation between α and δ (37% identity), their similar functional characteristics provide an excellent model for exploring structural correlates of specific ENaC biophysical and pharmacological properties. Moreover, the study of cellular mechanisms modulating the activity of different ENaC subunit combinations provides an opportunity to gain insight into the regulation of the channel. In this review, we examine the evolution of ENaC genes, channel subunit composition, the distinct functional and pharmacological features that δ confers to ENaC, and how this can be exploited to better understand this ion channel. Finally, we briefly consider possible functional roles of the ENaC δ-subunit.

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“…water content. The concept of dehydrated mucus due to hyperabsorption through the epithelial sodium channel (ENaC) (Boucher, 2007) has been widely accepted for CF airways; however, hyperabsorption does not seem to explain mucus aggregation in organs where there are no known mechanisms of fluid absorption, such as the pancreas (Novak & Hansen, 2002).…”

Section: Independent Impacts Of Hco 3 − and Fluid Secretionmentioning

confidence: 99%

A new role for bicarbonate secretion in cervico‐uterine mucus release

Muchekehu

Quinton

2010

The Journal of Physiology

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Cervical mucus thinning and release during the female reproductive cycle is thought to rely mainly on fluid secretion. However, we now find that mucus released from the murine reproductive tract critically depends upon concurrent bicarbonate (HCO 3 − ) secretion. Prostaglandin E 2 (PGE 2 )-and carbachol-stimulated mucus release was severely inhibited in the absence of serosal HCO 3 − , HCO 3 − transport, or functional cystic fibrosis transmembrane conductance regulator (CFTR). In contrast to mucus release, PGE 2 -and carbachol-stimulated fluid secretion was not dependent on bicarbonate or on CFTR, but was completely blocked by niflumic acid. We found stimulated mucus release was severely impaired in the cystic fibrosis F508 reproductive tract, even though stimulated fluid secretion was preserved. Thus, CFTR mutations and/or poor bicarbonate secretion may be associated with reduced female fertility associated with abnormal mucus and specifically, may account for the increased viscosity and lack of cyclical changes in cervical mucus long noted in women with cystic fibrosis.

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Where have all the Na+ channels gone? In search of functional ENaC in exocrine pancreas

Cited by 20 publications

References 34 publications

Heightened epithelial Na⁺ channel-mediated Na⁺ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia

Heightened epithelial Na⁺ channel-mediated Na⁺ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia

The epithelial sodium channel δ-subunit: new notes for an old song

A new role for bicarbonate secretion in cervico‐uterine mucus release

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Where have all the Na+ channels gone? In search of functional ENaC in exocrine pancreas

Cited by 20 publications

References 34 publications

Heightened epithelial Na+ channel-mediated Na+ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia

Heightened epithelial Na+ channel-mediated Na+ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia

The epithelial sodium channel δ-subunit: new notes for an old song

A new role for bicarbonate secretion in cervico‐uterine mucus release

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Product

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Heightened epithelial Na⁺ channel-mediated Na⁺ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia

Heightened epithelial Na⁺ channel-mediated Na⁺ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia