RT Journal Article
T1 Brugada syndrome trafficking-defective Nav1.5 channels can trap cardiac Kir2.1/2.2 channels.
A1 Pérez-Hernández, Marta
A1 Nieto Marín, Paloma
A1 Crespo García, María Teresa
A1 Tamargo Menéndez, Juan
A1 Caballero Collado, Ricardo
A1 Delpón Mosquera, María Eva
AB Cardiac Nav1.5 and Kir2.1–2.3 channels generate Na (INa) and inward rectifier K (IK1) currents, respectively. The functional INa and IK1 interplay is reinforced by the positive and reciprocal modulation between Nav15 and Kir2.1/2.2 channels to strengthen the control of ventricular excitability. Loss-of-function mutations in the SCN5A gene, which encodes Nav1.5 channels, underlie several inherited arrhythmogenic syndromes, including Brugada syndrome (BrS). We investigated whether the presence of BrS-associated mutations alters IK1 density concomitantly with INa density. Results obtained using mouse models of SCN5A haploinsufficiency, and the overexpression of native and mutated Nav1.5 channels in expression systems — rat ventricular cardiomyocytes and human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) — demonstrated that endoplasmic reticulum (ER) trafficking–defective Nav1.5 channels significantly decreased IK1, since they did not positively modulate Kir2.1/2.2 channels. Moreover, Golgi trafficking–defective Nav1.5 mutants produced a dominant negative effect on Kir2.1/2.2 and thus an additional IK1 reduction. Moreover, ER trafficking–defective Nav1.5 channels can be partially rescued by Kir2.1/2.2 channels through an unconventional secretory route that involves Golgi reassembly stacking proteins (GRASPs). Therefore, cardiac excitability would be greatly affected in subjects harboring Nav1.5 mutations with Golgi trafficking defects, since these mutants can concomitantly trap Kir2.1/2.2 channels, thus unexpectedly decreasing IK1 in addition to INa.
PB American Society for Clinical Investigation
YR 2018
FD 2018
LK https://hdl.handle.net/20.500.14352/92119
UL https://hdl.handle.net/20.500.14352/92119
LA eng
NO JCI Insight. 2018;3(18):e96291. https://doi.org/10.1172/jci.insight.96291.
NO Comunidad de Madrid
NO European Commission
NO Ministerio de Economía y Competitividad (España)
NO Instituto de Salud Carlos III
NO Fundación BBVA
NO Leducq foundation
DS Docta Complutense
RD 16 dic 2025