Membrane trafficking pathways regulating the epithelial Na⁺channel

Abstract

Renal Na+ reabsorption, facilitated by the epithelial Na+ channel (ENaC), is subject to multiple forms of control to ensure optimal body blood volume and pressure through altering both the ENaC population and activity at the cell surface. Here, the focus is on regulating the number of ENaCs present in the apical membrane domain through pathways of ENaC synthesis and targeting to the apical membrane as well as ENaC removal, recycling, and degradation. Finally, the mechanisms by which ENaC trafficking pathways are regulated are summarized.

Molecular characteristics and physiological roles of Na+–K+–Cl− cotransporter 2

“…There are additional lines of evidence to suggest that the trafficking machinery plays an important role in NKCC2 regulation by various hormones. While, for instance, aldosterone has been shown to downregulate NKCC2 expression in the TALH as part of the so‐called escape phenomenon (Madala Halagappa, Tiwari, Riazi, Hu, & Ecelbarger, 2008; Turban, Wang, & Knepper, 2003) and to exhibit purinergic‐dependent activity (Y. Zhang, Listhrop, Ecelbarger, & Kishore, 2011), both this hormone and purinergic agonists have also been shown to affect the abundance of other ion transport systems at the surface of the renal epithelium (Raghavan & Weisz, 2015; Ware, Rasulov, Cheung, Lott, & McDonald, 2020). In this regard, additionally, aldosterone has been found to increase phosphorylation and membrane abundance of NCC (van der Lubbe et al, 2011) and to coordinate WNK activity in several nephron segments (Susa et al, 2012).…”

Effects of syntaxins 2, 3, and 4 on rat and human epithelial sodium channel (ENaC) in Xenopus laevis oocytes

“…One-way ANOVA followed by Bonferroni's multiple comparison test with selected pairs, *p < 0.05, **p < 0.01, ***p < 0.001 strongly enhanced by long-term stimulation with cAMP [36]. Effects of Rab11a and Rab11b on ENaC activity indicate that recycling endosomes play a role in ENaC delivery to the plasma membrane [4,66]. Rab11a has been shown to increase ENaC activity in CHO cells [21], and a dominant negative form of Rab11a has been shown to inhibit ENaC-dependent sodium transport in mpkCCD cells [5].…”

“…This result suggests that syntaxin 3 does not inhibit channel retrieval but stimulates channel insertion. Delivery of ENaC to the plasma membrane may be directly from the Golgi apparatus, from the recycling pathway or from stored vesicles [4,66]. The relative importance of these delivery pathways is likely to be regulated according to physiological needs and probably varies in different tissues and cellular expression systems.…”

Essential requirement of complex number for oscillatory phenomenon in intracellular trafficking process

“…Epithelial Na + channel (ENaC) contributes to determination of the body fluid content through control of the amount of Na + reabsorption in the kidney, which is mainly regulated by the amount (number) of ENaC located on the plasma membrane of cortical tubules in the kidney [1] , [2] , [3] , [4] . The body fluid content is one of the most important key factors influencing blood pressure [4] , [5] , [6] , [7] , [8] , [9] , [10] .…”

“…The quantitative information is very useful to understand the molecular mechanism of the intracellular ENaC trafficking process. Biochemical, immunochemical and molecular biological approaches provide us with quantitative information on the amount of ENaC located on the plasma membrane [3] . However, the time resolution provided by these techniques is not high enough to quantitatively analyze the ENaC trafficking kinetics.…”