Cytosolic Na+ controls and epithelial Na+ channel via the Go guanine nucleotide-binding regulatory protein.

Background: Loss-of-function amyloid precursor protein (APP) and Nav1.6 transgenic mice share similar phenotypes. Results: APP interacts with Nav1.6 and enhances its cell surface expression through a G o -coupled JNK pathway. Conclusion: APP regulates Nav1.6 function, likely through a G o -coupled JNK pathway. Significance: This finding advances the current understanding of APP functions and has implications for novel therapies for neurodegenerative disorders.

Section: Discussionsupporting

confidence: 80%

Section: App Is Colocalized With Nav16 In Mouse Cortical Neurons-mentioning

confidence: 99%

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Liu

Tan

Xiao

et al. 2015

“…Although a variety of molecules have been implicated (e.g. G o guanine nucleotidebinding regulatory proteins, Ca 2ϩ , ATP, pH, and AKAP15), the data in the literature are conflicting (12,15,(33)(34)(35).…”

Section: Figure 5 Namentioning

confidence: 99%

“…By countering changes in Na ϩ delivery to the distal nephron, this pathway functions to maintain Na ϩ homeostasis. Previous work indicates that both extracellular Na ϩ ("Na ϩ self-inhibition" (10,11,18)) and intracellular Na ϩ ("Na ϩ feedback inhibition" (12)(13)(14)(15)(16)) regulate ENaC activity. However, an understanding of the underlying mechanisms has remained elusive.…”

Section: Transport Of Namentioning

confidence: 99%

Intracellular Sodium Regulates Proteolytic Activation of the Epithelial Sodium Channel

Knight

Wentzlaff

Snyder

2008

Na؉ transport across epithelia is mediated in part by the epithelial Na ؉ channel ENaC. Previous work indicates that Na ؉ is an important regulator of ENaC, providing a negative feedback mechanism to maintain Na ؉ homeostasis. ENaC is synthesized as an inactive precursor, which is activated by proteolytic cleavage of the extracellular domains of the ␣ and ␥ subunits. Here we found that Na ؉ regulates ENaC in part by altering proteolytic activation of the channel. When the Na ؉ concentration was low, we found that the majority of ENaC at the cell surface was in the cleaved/active state. As Na ؉ increased, there was a dosedependent decrease in ENaC cleavage and, hence, ENaC activity. This Na ؉ effect was dependent on Na ؉ permeation; cleavage was increased by the ENaC blocker amiloride and by a mutation that decreases ENaC activity (␣ H69A ) and was reduced by a mutation that activates ENaC (␤ S520K ). Moreover, the Na ؉ ionophore monensin reversed the effect of the inactivating mutation (␣ H69A ) on ENaC cleavage, suggesting that intracellular Na ؉ regulates cleavage. Na ؉ did not alter activity of Nedd4-2, an E3 ubiquitin ligase that modulates ENaC cleavage, but Na ؉ reduced ENaC cleavage by exogenous trypsin. Our findings support a model in which intracellular Na ؉ regulates cleavage by altering accessibility of ENaC cleavage sites to proteases and provide a molecular explanation for the earlier observation that intracellular Na ؉ inhibits Na ؉ transport via ENaC (Na ؉ feedback inhibition).Transport of Na ϩ across epithelia is critical to maintain Na ϩ homeostasis. Defects in Na ϩ transport cause inherited forms of hypertension (e.g. Liddle syndrome) and hypotension (pseudohypoaldosteronism type 1) (1). In the distal nephron of the kidney, lung, colon, and sweat duct, transport is mediated by the epithelial Na ϩ channel ENaC, a heterotrimer composed of homologous ␣, ␤, and ␥ subunits (2-5). ENaC is located at the apical membrane, where it functions as a conduit for Na ϩ to enter the cell (reviewed in Refs. 6 and 7). Coupled with Na ϩ exit at the basolateral membrane via the Na ϩ -K ϩ -ATPase, ENaC provides a pathway for Na ϩ reabsorption across these tissues. Although Na ϩ is the permeant ion for this pathway, Na ϩ also regulates its own transport through negative feedback mechanisms (8 -16). Under conditions of Na ϩ /volume excess, the Na ϩ concentration in the distal nephron is high (Ͼ50 mM) (17), which inhibits ENaC in order to minimize Na ϩ reabsorption. Conversely, under conditions of Na ϩ /volume depletion, the Na ϩ concentration is low (ϳ1 mM) (17), which activates ENaC to maximize Na ϩ reabsorption. By countering changes in Na ϩ delivery to the distal nephron, this pathway functions to maintain Na ϩ homeostasis. Previous work indicates that both extracellular Na ϩ ("Na ϩ self-inhibition" (10, 11, 18)) and intracellular Na ϩ ("Na ϩ feedback inhibition" (12-16)) regulate ENaC activity. However, an understanding of the underlying mechanisms has remained elusive.In this work, we tested the hypothesis that N...

“…It is not dependent on Na ϩ influx, nor on intracellular Na ϩ concentration. On the other hand, increases in intracellular Na ϩ concentration result in feedback inhibition of ENaC (11)(12)(13)(14). The latter is likely due to a reduction of channel density at the plasma membrane (2).…”

Section: Epithelial Namentioning

confidence: 99%

Extracellular Histidine Residues Crucial for Na+ Self-inhibition of Epithelial Na+ Channels

Sheng

Bruns²,

Kleyman

2004

109

Epithelial Na؉ channels (ENaC) participate in the regulation of extracellular fluid volume homeostasis and blood pressure. Channel activity is regulated by both extracellular and intracellular Na ؉ . The down-regulation of ENaC activity by external Na ؉ is referred to as Na ؉ self-inhibition. We investigated the structural determinants of Na ؉ self-inhibition by expressing wildtype or mutant ENaCs in Xenopus oocytes and analyzing changes in whole-cell Na ؉ currents following a rapid increase of bath Na ؉ concentration. Our results indicated that wild-type mouse ␣␤␥ENaC has intrinsic Na ؉ self-inhibition similar to that reported for human, rat, and Xenopus ENaCs. Mutations at His 239 (␥H239R, ␥H239D, and ␥H239C) in the extracellular loop of the ␥ENaC subunit prevented Na ؉ self-inhibition whereas mutations of the corresponding His 282 in ␣ENaC (␣H282D, ␣H282R, ␣H282W, and ␣H282C) significantly enhanced Na ؉ self-inhibition. These results suggest that these two histidine residues within the extracellular loops are crucial structural determinants for Na ؉ self-inhibition.