RT Journal Article
T1 Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1
T2 Regulación del canal de sodio dependiente de voltaje NaV1.1 por AKT1
A1 Arribas Blázquez, Marina
A1 Piniella, Dolores
A1 Olivos Ore, Luis Alcides
A1 Bartolomé-Martín, David
A1 Leite, Cristiana
A1 Giménez, Cecilia
A1 Rodríguez Artalejo, Antonio
A1 Zafra, Francisco
AB The voltage-sensitive sodium channel NaV1.1 plays a critical role in regulating excitability of GABAergic neurons and mutations in the corresponding gene are associated to Dravet syndrome and other forms of epilepsy. The activity of this channel is regulated by several protein kinases. To identify novel regulatory kinases we screened a library of activated kinases and we found that AKT1 was able to directly phosphorylate NaV1.1. In vitro kinase assays revealed that the phosphorylation site was located in the C-terminal part of the large intracellular loop connecting domains I and II of NaV1.1, a region that is known to be targeted by other kinases like PKA and PKC. Electrophysiological recordings revealed that activated AKT1 strongly reduced peak Na+ currents and displaced the inactivation curve to more negative potentials in HEK-293 cell stably expressing NaV1.1. These alterations in current amplitude and steady-state inactivation were mimicked by SC79, a specific activator of AKT1, and largely reverted by triciribine, a selective inhibitor. Neurons expressing endogenous NaV1.1 in primary cultures were identified by expressing a fluorescent protein under the NaV1.1 promoter. There, we also observed a strong decrease in the current amplitude after addition of SC79, but small effects on the inactivation parameters. Altogether, we propose a novel mechanism that might regulate the excitability of neural networks in response to AKT1, a kinase that plays a pivotal role under physiological and pathological conditions, including epileptogenesis.
PB Elsevier
SN 0028-3908
YR 2021
FD 2021
LK https://hdl.handle.net/20.500.14352/94606
UL https://hdl.handle.net/20.500.14352/94606
LA eng
NO Arribas-Blázquez, Marina, et al. «Regulation of the Voltage-Dependent Sodium Channel NaV1.1 by AKT1». Neuropharmacology, vol. 197, octubre de 2021, p. 108745. https://doi.org/10.1016/j.neuropharm.2021.108745.
NO Credit authorship contribution statement Marina Arribas-Blázquez: performed research. Dolores Piniella: performed research. Luis A. Olivos-Oré: analyzed data and wrote the paper, performed research. David Bartolomé-Martín: performed research. Cristiana Leite: performed research. Cecilio Giménez: designed research. Antonio R. Artalejo: designed research, analyzed data and wrote the paper. Francisco Zafra: designed research, analyzed data and wrote the paper.
NO Ministerio de Economía y Competitividad (España)
NO Fundación Síndrome de Dravet
DS Docta Complutense
RD 10 abr 2025