The epithelial Na+ channel (original) (raw)
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Epithelial Na+ Channels Are Activated by Laminar Shear Stress
Journal of Biological Chemistry, 2003
The degenerin/epithelial Na ؉ channel (ENaC) superfamily is a group of structurally related ion channels that are involved in diverse biological processes, including responses to mechanical stimuli. In renal cortical collecting ducts, changes in rates of perfusion affect Na ؉ reabsorption through an amiloride-sensitive pathway, suggesting that ENaC may be a mechanosensitive channel. In this study, we examined whether ENaC expressed in oocytes is regulated by laminar shear stress (LSS). A 1.8-mm (internal diameter) perfusion pipette was placed within 0.5-1.0 mm of the oocyte to provide laminar flow across the oocyte surface. LSS induced a dose-dependent and reversible increase in benzamilsensitive whole cell Na ؉ currents in oocytes expressing ␣␥ ENaC. The half-time for activation by LSS was ϳ5 s. Repetitive stimulation by LSS of oocytes expressing ENaC was associated with a reduction in the response to LSS. Oocytes expressing ␣S518K␥, a pore region mutant with a high open probability, were insensitive to LSS. We demonstrated previously that channels with a Cys residue introduced at position ␣Ser-580 had a low open probability, but, following modification by [2-(trimethylammonium)ethyl]methanethiosulfonate bromide (MTSET), channels exhibited a high open probability. Oocytes expressing ␣S580C␥ ENaC respond to LSS similar to wild type; however, covalent modification by MT-SET largely eliminated the response to LSS. Our results suggest that shear stress activates ENaC by modifying the gating properties of the channel.
Epithelial sodium channel (ENaC) in GtoPdb v.2021.2
IUPHAR/BPS Guide to Pharmacology CITE, 2021
The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon, and some other organs [9, 13, 22, 21, 42]. In these epithelia, Na+ ions flow from the extracellular fluid into the cytoplasm of epithelial cells via ENaC. The Na+ ions are then pumped out of the cytoplasm into the interstitial fluid by the Na+/K+ ATPase located on the basolateral membrane [36]. As Na+ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na+ flow is accompanied by a flow of water accompanying Na+ ions [6]. Thus, ENaC has a central role in regulating ECF volume and blood pressure, primarily via its function in the kidney [37]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angiotensin-aldosterone system, and other factors involved in electrolyte homeostasis [37, 30]. In ...
Epithelial sodium channel modulates platelet collagen activation
European Journal of Cell Biology, 2014
Activated platelets adhere to the exposed subendothelial extracellular matrix and undergo a rapid cytoskeletal rearrangement resulting in shape change and release of their intracellular dense and alpha granule contents to avoid hemorrhage. A central step in this process is the elevation of the intracellular Ca 2+ concentration through its release from intracellular stores and on throughout its influx from the extracellular space. The Epithelial sodium channel (ENaC) is a highly selective Na + channel involved in mechanosensation, nociception, fluid volume homeostasis, and control of arterial blood pressure. The present study describes the expression, distribution, and participation of ENaC in platelet migration and granule secretion using pharmacological inhibition with amiloride. Our biochemical and confocal analysis in suspended and adhered platelets suggests that ENaC is associated with Intermediate filaments (IF) and with Dystrophin-associated proteins (DAP) via ␣-syntrophin and -dystroglycan. Migration assays, quantification of soluble P-selectin, and serotonin release suggest that ENaC is dispensable for migration and alpha and dense granule secretion, whereas Na + influx through this channel is fundamental for platelet collagen activation.
Canadian Journal of Physiology and Pharmacology, 2012
The vascular endothelium plays a critical role in vascular health by controlling arterial diameter, regulating local cell growth, and protecting blood vessels from the deleterious consequences of platelet aggregation and activation of inflammatory responses. Circulating chemical mediators and physical forces act directly on the endothelium to release diffusible relaxing factors, such as nitric oxide (NO), and to elicit hyperpolarization of the endothelial cell membrane potential, which can spread to the surrounding smooth muscle cells via gap junctions. Endothelial hyperpolarization, mediated by activation of calcium-activated potassium (K Ca ) channels, has generally been regarded as a distinct pathway for smooth muscle relaxation. However, recent evidence supports a role for endothelial K Ca channels in production of endothelium-derived NO, and indicates that pharmacological activation of these channels can enhance NO-mediated responses. In this review we summarize the current data on the functional role of endothelial K Ca channels in regulating NO-mediated changes in arterial diameter and NO production, and explore the tempting possibility that these channels may represent a novel avenue for therapeutic intervention in conditions associated with reduced NO availability such as hypertension, hypercholesterolemia, smoking, and diabetes mellitus.
The epithelial sodium channel in inflammation and blood pressure modulation
Frontiers in Cardiovascular Medicine
A major regulator of blood pressure and volume homeostasis in the kidney is the epithelial sodium channel (ENaC). ENaC is composed of alpha(α)/beta(β)/gamma(γ) or delta(δ)/beta(β)/gamma(γ) subunits. The δ subunit is functional in the guinea pig, but not in routinely used experimental rodent models including rat or mouse, and thus remains the least understood of the four subunits. While the δ subunit is poorly expressed in the human kidney, we recently found that its gene variants are associated with blood pressure and kidney function. The δ subunit is expressed in the human vasculature where it may influence vascular function. Moreover, we recently found that the δ subunit is also expressed human antigen presenting cells (APCs). Our studies indicate that extracellular Na+ enters APCs via ENaC leading to inflammation and salt-induced hypertension. In this review, we highlight recent findings on the role of extra-renal ENaC in inflammation, vascular dysfunction, and blood pressure mod...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2007
Epithelial cells are exposed to a variety of mechanical forces, but little is known about the impact of these forces on epithelial ion channels. Here we show that mechanical activation of epithelial sodium channels (ENaCs), which are essential for electrolyte and water balance, occurs via an increased ion channel open probability. ENaC activity of heterologously expressed rat (rENaC) and Xenopus (xENaC) orthologs was measured by whole-cell as well as single-channel recordings. Laminar shear stress (LSS), producing shear forces in physiologically relevant ranges, was used to mechanically stimulate ENaCs and was able to activate ENaC currents in whole-cell recordings. Preceding pharmacological activation of rENaC with Zn2+ and xENaC with gadolinium and glibenclamide largely prevented LSS-activated currents. In contrast, proteolytic cleavage with trypsin potentiated the LSS effect on rENaC whereas the LSS effect on xENaC was reversed (inhibition of xENaC current). Further, we found tha...
Rapid Translocation and Insertion of the Epithelial Na+ Channel in Response to RhoA Signaling
Journal of Biological Chemistry, 2006
Activity of the epithelial Na ؉ channel (ENaC) is limiting for Na ؉ absorption across many epithelia. Consequently, ENaC is a central effector impacting systemic blood volume and pressure. . The abbreviations used are: ENaC, epithelial Na ϩ channel; mENaC, mouse ENaC; PI3K, phosphatidylinositol 3-kinase; PI(4,5)P 2 , phosphatidylinositol 4,5-biphosphate; CHO, Chinese hamster ovary; eYFP, enhanced yellow fluorescent protein; eCFP, enhanced cyan fluorescent protein; TIRF, total internal reflection fluorescence; PI(4)P5K, phosphatidylinositol-4phosphate 5-kinase; pF, picofarad; HA, hemagglutinin; CA, constitutively active; DN, dominant negative.