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Open AccessArticle

Functional Consequences of the SCN5A-p.Y1977N Mutation within the PY Ubiquitylation Motif: Discrepancy between HEK293 Cells and Transgenic Mice

1
Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 Amsterdam, The Netherlands
2
Ion Channels and Channelopathies Laboratory, Institute for Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern, Switzerland
3
Departments of Pediatrics & Medicine, Columbia University Medical Center, 1150 St Nicholas Avenue, New York, NY 10032, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(20), 5033; https://doi.org/10.3390/ijms20205033
Received: 5 September 2019 / Revised: 4 October 2019 / Accepted: 6 October 2019 / Published: 11 October 2019
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2019)
Dysfunction of the cardiac sodium channel Nav1.5 (encoded by the SCN5A gene) is associated with arrhythmias and sudden cardiac death. SCN5A mutations associated with long QT syndrome type 3 (LQT3) lead to enhanced late sodium current and consequent action potential (AP) prolongation. Internalization and degradation of Nav1.5 is regulated by ubiquitylation, a post-translational mechanism that involves binding of the ubiquitin ligase Nedd4-2 to a proline-proline-serine-tyrosine sequence of Nav1.5, designated the PY-motif. We investigated the biophysical properties of the LQT3-associated SCN5A-p.Y1977N mutation located in the Nav1.5 PY-motif, both in HEK293 cells as well as in newly generated mice harboring the mouse homolog mutation Scn5a-p.Y1981N. We found that in HEK293 cells, the SCN5A-p.Y1977N mutation abolished the interaction between Nav1.5 and Nedd4-2, suppressed PY-motif-dependent ubiquitylation of Nav1.5, and consequently abrogated Nedd4-2 induced sodium current (INa) decrease. Nevertheless, homozygous mice harboring the Scn5a-p.Y1981N mutation showed no electrophysiological alterations nor changes in AP or (late) INa properties, questioning the in vivo relevance of the PY-motif. Our findings suggest the presence of compensatory mechanisms, with additional, as yet unknown, factors likely required to reduce the “ubiquitylation reserve” of Nav1.5. Future identification of such modulatory factors may identify potential triggers for arrhythmias and sudden cardiac death in the setting of LQT3 mutations. View Full-Text
Keywords: SCN5A; ubiquitylation; long QT syndrome; sodium current; Nedd4-2; action potential; patch-clamp; mouse model SCN5A; ubiquitylation; long QT syndrome; sodium current; Nedd4-2; action potential; patch-clamp; mouse model
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Casini, S.; Albesa, M.; Wang, Z.; Portero, V.; Ross-Kaschitza, D.; Rougier, J.-S.; Marchal, G.A.; Chung, W.K.; Bezzina, C.R.; Abriel, H.; Remme, C.A. Functional Consequences of the SCN5A-p.Y1977N Mutation within the PY Ubiquitylation Motif: Discrepancy between HEK293 Cells and Transgenic Mice. Int. J. Mol. Sci. 2019, 20, 5033.

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