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Shear force sensing of epithelial Na+ channel (ENaC) relies on N-glycosylated asparagines in the palm and knuckle domains of ?ENaC.


ABSTRACT: Mechanosensitive ion channels are crucial for normal cell function and facilitate physiological function, such as blood pressure regulation. So far little is known about the molecular mechanisms of how channels sense mechanical force. Canonical vertebrate epithelial Na+ channel (ENaC) formed by ?-, ?-, and ?-subunits is a shear force (SF) sensor and a member of the ENaC/degenerin protein family. ENaC activity in epithelial cells contributes to electrolyte/fluid-homeostasis and blood pressure regulation. Furthermore, ENaC in endothelial cells mediates vascular responsiveness to regulate blood pressure. Here, we provide evidence that ENaC's ability to mediate SF responsiveness relies on the "force-from-filament" principle involving extracellular tethers and the extracellular matrix (ECM). Two glycosylated asparagines, respectively their N-glycans localized in the palm and knuckle domains of ?ENaC, were identified as potential tethers. Decreased SF-induced ENaC currents were observed following removal of the ECM/glycocalyx, replacement of these glycosylated asparagines, or removal of N-glycans. Endothelial-specific overexpression of ?ENaC in mice induced hypertension. In contrast, expression of ?ENaC lacking these glycosylated asparagines blunted this effect. In summary, glycosylated asparagines in the palm and knuckle domains of ?ENaC are important for SF sensing. In accordance with the force-from-filament principle, they may provide a connection to the ECM that facilitates vascular responsiveness contributing to blood pressure regulation.

SUBMITTER: Knoepp F 

PROVIDER: S-EPMC6955349 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Shear force sensing of epithelial Na<sup>+</sup> channel (ENaC) relies on <i>N</i>-glycosylated asparagines in the palm and knuckle domains of αENaC.

Knoepp Fenja F   Ashley Zoe Z   Barth Daniel D   Baldin Jan-Peter JP   Jennings Michael M   Kazantseva Marina M   Saw Eng Leng EL   Katare Rajesh R   Alvarez de la Rosa Diego D   Weissmann Norbert N   Fronius Martin M  

Proceedings of the National Academy of Sciences of the United States of America 20191223 1


Mechanosensitive ion channels are crucial for normal cell function and facilitate physiological function, such as blood pressure regulation. So far little is known about the molecular mechanisms of how channels sense mechanical force. Canonical vertebrate epithelial Na<sup>+</sup> channel (ENaC) formed by α-, β-, and γ-subunits is a shear force (SF) sensor and a member of the ENaC/degenerin protein family. ENaC activity in epithelial cells contributes to electrolyte/fluid-homeostasis and blood p  ...[more]

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