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

Autor:	Knoepp F; Excellence-Cluster Cardio-Pulmonary Institute, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Justus-Liebig University Giessen, D-35392 Giessen, Germany., Ashley Z; Department of Physiology, University of Otago, 9016 Dunedin New Zealand.; HeartOtago, University of Otago, 9016 Dunedin, New Zealand., Barth D; Department of Physiology, University of Otago, 9016 Dunedin New Zealand.; HeartOtago, University of Otago, 9016 Dunedin, New Zealand., Baldin JP; Department of Physiology, University of Otago, 9016 Dunedin New Zealand.; HeartOtago, University of Otago, 9016 Dunedin, New Zealand., Jennings M; Department of Physiology, University of Otago, 9016 Dunedin New Zealand., Kazantseva M; Department of Physiology, University of Otago, 9016 Dunedin New Zealand., Saw EL; Department of Physiology, University of Otago, 9016 Dunedin New Zealand.; HeartOtago, University of Otago, 9016 Dunedin, New Zealand., Katare R; Department of Physiology, University of Otago, 9016 Dunedin New Zealand.; HeartOtago, University of Otago, 9016 Dunedin, New Zealand., Alvarez de la Rosa D; Department of Physiology, Institute of Biomedical Technology, University of Laguna, E-38071 La Laguna, Spain., Weissmann N; Excellence-Cluster Cardio-Pulmonary Institute, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Justus-Liebig University Giessen, D-35392 Giessen, Germany., Fronius M; Department of Physiology, University of Otago, 9016 Dunedin New Zealand; martin.fronius@otago.ac.nz.; HeartOtago, University of Otago, 9016 Dunedin, New Zealand.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jan 07; Vol. 117 (1), pp. 717-726. Date of Electronic Publication: 2019 Dec 23.
DOI:	10.1073/pnas.1911243117
Abstrakt:	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 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 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 αENaC, 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 αENaC in mice induced hypertension. In contrast, expression of αENaC lacking these glycosylated asparagines blunted this effect. In summary, glycosylated asparagines in the palm and knuckle domains of αENaC 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. Competing Interests: The authors declare no competing interest. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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