Characteristics and Pharmacological Regulation of Epithelial Na+ Channel (ENaC) and Epithelial Na+ Transport

Marunaka, Yoshinori

doi:10.1254/jphs.14r01sr

Cited by 31 publications

(46 citation statements)

References 147 publications

(134 reference statements)

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“…Although A6 cells are not mammalian cell line, A6 cells show similar behaviors and responses to environmental changes such as osmolality and hormones such as aldosterone and arginine vasopressin via V 2 receptor as an antidiuretic hormone observed in mammalian cells [3,10,13,14,[52][53][54][55][56][57][58][59][60][61][62]. In addition to these factors, A6 cells show a change in ENaC-mediated Na + transport responding to hypotonicity via modification of intracellular ENaC trafficking as shown in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Epithelial Na + reabsorption is a two step process: 1) the first is the entry of Na + across the apical membrane of epithelial cells into the intracellular space via epithelial Na + channels (ENaC) located at the apical membrane, and 2) the second step is transport of Na + from the intracellular space across the basolateral membrane of epithelial cells via the basolateral Na + ,K + -pump [3,4]. The rate-limiting step in transepithelial Na + transport is generally considered to be the Na + entry step through ENaC rather than the Na + extrusion step through the Na + ,K + -pump.…”

Section: Introductionmentioning

confidence: 99%

“…The rate-limiting step in transepithelial Na + transport is generally considered to be the Na + entry step through ENaC rather than the Na + extrusion step through the Na + ,K + -pump. Therefore, transepithelial Na + transport depends on the amount of Na + entry via ENaC across the apical membrane, which is controlled by the number of ENaCs and the activity (open probability) of individual ENaC located at the apical membrane [3,[11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Aprotinin, a Protease Inhibitor, Action on the Trafficking of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells Using a Mathematical Model

Sasamoto¹,

Marunaka²,

Niisato

et al. 2017

Cell Physiol Biochem

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Background/Aim: Epithelial Na⁺ channels (ENaC) play a crucial role in control of blood pressure by regulating renal Na⁺ reabsorption. Intracellular trafficking of ENaC is one of the key regulators of ENaC function, but a quantitative description of intracellular recycling of endogenously expressed ENaC is unavailable. We attempt here to provide a model for intracellular recycling after applying a protease inhibitor under hypotonic conditions. Methods: We simulated the ENaC-mediated Na⁺ transport in renal epithelial A6 cells measured as short-circuit currents using a four-state mathematical ENaC trafficking model. Results: We developed a four-state mathematical model of ENaC trafficking in the cytosol of renal epithelial cells that consists of: an insertion state of ENaC that can be trafficked to the apical membrane state (insertion rate); an apical membrane state of ENaC conducting Na⁺ across the apical membrane; a recycling state containing ENaC that are retrieved from the apical membrane state (endocytotic rate) and then to the insertion state (recycling rate) communicating with the apical membrane state or to a degradation state (degradation rate). We studied the effect of aprotinin (a protease inhibitor) blocking protease-induced cleavage of the extracellular loop of γ ENaC subunit on the rates of intracellular ENaC trafficking using the above-defined four-state mathematical model of ENaC trafficking and the recycling number relative to ENaC staying in the apical membrane. We found that aprotinin significantly reduced the insertion rate of ENaC to the apical membrane by 40%, the recycling rate of ENaC by 81%, the cumulative time of an individual ENaC staying in the apical membrane by 32%, the cumulative life-time after the first endocytosis of ENaC by 25%, and the cumulative Na⁺ absorption by 31%. The most interesting result of the present study is that cleavage of ENaC affects the intracellular ENaC trafficking rate and determines the residency time of ENaC, indicating that more active cleaved ENaCs stay longer at the apical membrane contributing to transcellular Na⁺ transport via an increase in recycling of ENaC to the apical membrane. Conclusion: The extracellular protease-induced cleavage of the extracellular loop of γ ENaC subunit increases transcellular epithelial Na⁺ transport by elevating the recycling rate of ENaC due to an increase in the recycling rate of ENaCs associated with increases in the insertion rate of ENaC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of Aprotinin, a Protease Inhibitor, Action on the Trafficking of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells Using a Mathematical Model

Sasamoto¹,

Marunaka²,

Niisato

et al. 2017

Cell Physiol Biochem

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“…This ENaC-mediated transepithelial Na + transport requires the two steps across the apical and basolateral membranes of epithelial cells: 1) the first step is the entry of Na + across the apical membrane of epithelial cells into the intracellular space via ENaCs expressed at the apical membrane, and 2) the second step is the extrusion of Na + from the intracellular space across the basolateral membrane of epithelial cells mediated by the basolateral Na + ,K + -pump located at the basolateral membrane [3,4]. It is generally considered that the rate-limiting step in the ENaC-mediated transepithelial Na + transport is the Na + entry through the apical-membrane-located ENaC rather than the Na + extrusion mediated by the basolateral-membrane-located Na + ,K + -pump.…”

Section: Introductionmentioning

confidence: 99%

Action of Protein Tyrosine Kinase Inhibitors on the Hypotonicity-Stimulated Trafficking Kinetics of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells: Analysis Using a Mathematical Model

Marunaka

Taruno

Yamamoto

et al. 2018

Cell Physiol Biochem

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Background/Aims: Epithelial Na₊ channels (ENaCs) play crucial roles in control of blood pressure by determining the total amount of renal Na₊ reabsorption, which is regulated by various factors such as aldosterone, vasopressin, insulin and osmolality. The intracellular trafficking process of ENaCs regulates the amount of the ENaC-mediated Na₊ reabsorption in the collecting duct of the kidney mainly by determining the number of ENaC expressed at the apical membrane of epithelial cells. Although we previously reported protein tyrosine kinases (PTKs) contributed to the ENaC-mediated epithelial Na₊ reabsorption, we have no information on the role of PTKs in the intracellular ENaC trafficking. Methods: Using the mathematical model recently established in our laboratory, we studied the effect of PTKs inhibitors (PTKIs), AG1296 (10 µM: an inhibitor of the PDGF receptor (PDGFR)) and AG1478 (10 µM: an inhibitor of the EGF receptor (EGFR)) on the rates of the intracellular ENaC trafficking in renal epithelial A6 cells endogenously expressing ENaCs. Results: We found that application of PTKIs significantly reduced the insertion rate of ENaC to the apical membrane by 56%, the recycling rate of ENaC by 83%, the cumulative time of an individual ENaC staying in the apical membrane by 27%, the whole life-time after the first insertion of ENaC by 47%, and the cumulative Na₊ absorption by 61%, while the degradation rate was increased to 3.8-fold by application of PTKIs. These observations indicate that PTKs contribute to the processes of insertion, recycling and degradation of ENaC in the intracellular trafficking process under a hypotonic condition. Conclusion: The present study indicates that application of EGFR and PDGFR-inhibitable PTKIs reduced the insertion rate (k_I), and the recycling rate (k_R) of ENaCs, but increased degradation rate (k_D) in renal A6 epithelial cells under a hypotonic condition. These observations indicate that hypotonicity increases the surface expression of ENaCs by increasing the insertion rate (k_I) and the recycling rate (k_R) of ENaCs associated with a decrease in the degradation rate but without any significant effects on the endocytotic rate (k_E) in EGFR and PDGFR-related PTKs-mediated pathways.

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“…Na + uptake (absorption) in the colon (1)(2)(3) and Na + reabsorption in the kidney (4-7) are conducted by epithelial Na + transport (Na + transport across epithelial cells) via epithelial Na + channel (ENaC) (8), which was cloned from rat distal colon (1,2). The epithelial Na + transport via ENaC is one of the most important factors controlling the adequate volume of fluids covering the apical surface of alveolar epithelial cells of the lung, which is essentially required to keep normal gas exchange across alveolar epithelium (9)(10)(11) and prevent the body from viral and bacterial infection (9)(10)(11).…”

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confidence: 99%

Na+ homeostasis by epithelial Na+ channel (ENaC) and Nax channel (Nax): cooperation of ENaC and Nax

Marunaka¹,

Marunaka²,

Sun³

et al. 2016

Ann. Transl. Med.

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Characteristics and Pharmacological Regulation of Epithelial Na+ Channel (ENaC) and Epithelial Na+ Transport

Cited by 31 publications

References 147 publications

Analysis of Aprotinin, a Protease Inhibitor, Action on the Trafficking of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells Using a Mathematical Model

Analysis of Aprotinin, a Protease Inhibitor, Action on the Trafficking of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells Using a Mathematical Model

Action of Protein Tyrosine Kinase Inhibitors on the Hypotonicity-Stimulated Trafficking Kinetics of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells: Analysis Using a Mathematical Model

Na+ homeostasis by epithelial Na+ channel (ENaC) and Nax channel (Nax): cooperation of ENaC and Nax

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