RT Journal Article
T1 Nav1.5 N-terminal domain binding to α1-syntrophin increases membrane density of human Kir2.1, Kir2.2 and Nav1.5 channels
A1 Matamoros Campos, Marcos
A1 Pérez Hernández, Marta
A1 Amorós García, Irene
A1 Barana Muñoz, Adriana
A1 Núñez, Mercedes
A1 Ponce Balbuena, Daniela
A1 Sacristán, Sandra
A1 Gómez García, Ricardo
A1 Tamargo Menéndez, Juan
A1 Caballero Collado, Ricardo
A1 Jalife, José
A1 Delpón Mosquera, María Eva
AB Aims: Cardiac excitability and refractoriness are largely determined by the function and number of inward rectifier K⁺ channels (Kir2.1-2.3), which are differentially expressed in the atria and ventricles, and Nav1.5 channels. We have focused on how Nav1.5 and Kir2.x function within a macromolecular complex by elucidating the molecular determinants that govern Nav1.5/Kir2.x reciprocal modulation.Methods and results: The results demonstrate that there is an unexpected 'internal' PDZ-like binding domain located at the N-terminus of the Nav1.5 channel that mediates its binding to α1-syntrophin. Nav1.5 N-terminal domain, by itself (the 132 aa peptide) (Nter), exerts a 'chaperone-like' effect that increases sodium (I(Na)) and inward rectifier potassium (I(K1)) currents by enhancing the expression of Nav1.5, Kir2.1, and Kir2.2 channels as demonstrated in Chinese hamster ovary (CHO) cells and in rat cardiomyocytes. Site-directed mutagenesis analysis demonstrates that the Nter chaperone-like effect is determined by Serine 20. Nav1.5-Kir2.x reciprocal positive interactions depend on a specific C-terminal PDZ-binding domain sequence (SEI), which is present in Kir2.1 and Kir2.2 channels but not in Kir2.3. Therefore, in human atrial myocytes, the presence of Kir2.3 isoforms precludes reciprocal I(K1)-INa density modulation. Moreover, results in rat and human atrial myocytes demonstrate that binding to α1-syntrophin is necessary for the Nav1.5-Kir2.x-positive reciprocal modulation.Conclusions: The results demonstrate the critical role of the N-terminal domain of Nav1.5 channels in Nav1.5-Kir2.x-reciprocal interactions and suggest that the molecular mechanisms controlling atrial and ventricular cellular excitability may be different.Keywords: Inward rectifier current; Kir2.x; Sodium current; α1-syntrophin.
PB Oxford University Press
SN 1755-3245
YR 2016
FD 2016-05-15
LK https://hdl.handle.net/20.500.14352/92010
UL https://hdl.handle.net/20.500.14352/92010
LA eng
NO Marcos Matamoros, Marta Pérez-Hernández, Guadalupe Guerrero-Serna, Irene Amorós, Adriana Barana, Mercedes Núñez, Daniela Ponce-Balbuena, Sandra Sacristán, Ricardo Gómez, Juan Tamargo, Ricardo Caballero, José Jalife, Eva Delpón, Nav1.5 N-terminal domain binding to α1-syntrophin increases membrane density of human Kir2.1, Kir2.2 and Nav1.5 channels, Cardiovascular Research, Volume 110, Issue 2, 15 May 2016, Pages 279–290, https://doi.org/10.1093/cvr/cvw009
NO Ministerio de Economía y Competitividad
NO Instituto de Salud Carlos III
NO Comunidad Autónoma de Madrid
NO Mutua Madrileña
NO BBVA
NO Almirall Foundations
NO National Heart Lung and Blood Institute of the US National Institutes of Health
DS Docta Complutense
RD 6 abr 2025