Abstract
In neurons, changes in Akt activity have been detected in response to the stimulation of transmembrane receptors. However, the mechanisms that lead to changes in neuronal function upon Akt inhibition are still poorly understood. In the present study, we interrogate how Akt inhibition could affect the activity of the neuronal Nav channels with while impacting intrinsic excitability. To that end, we employed voltage-clamp electrophysiological recordings in heterologous cells expressing the Nav1.6 channel isoform and in hippocampal CA1 pyramidal neurons in the presence of triciribine, an inhibitor of Akt. We showed that in both systems, Akt inhibition resulted in a potentiation of peak transient Na+ current (INa) density. Akt inhibition correspondingly led to an increase in the action potential firing of the CA1 pyramidal neurons that was accompanied by a decrease in the action potential current threshold. Complementary confocal analysis in the CA1 pyramidal neurons showed that the inhibition of Akt is associated with the lengthening of Nav1.6 fluorescent intensity along the axonal initial segment (AIS), providing a mechanism for augmented neuronal excitability. Taken together, these findings provide evidence that Akt-mediated signal transduction might affect neuronal excitability in a Nav1.6-dependent manner.
Highlights
The serine/threonine kinase Akt (protein kinase B (PKB)) is a ubiquitously expressed enzyme that plays essential roles in cell growth, survival, motility, and regulation of metabolism, and homeostasis in almost all organs including, the brain [1,2,3,4,5,6,7,8,9]
Once Akt translocates to the cell membrane, it is activated by a multistep phosphorylation process that results in phosphorylation of Thr308 by phosphoinositide-dependent kinase 1 (PDK1) and Ser473 by phosphoinositide-dependent kinase 2 (PDK2) [17,19,20,21,22]
We show that the observed changes in CA1 pyramidal neuron activity are accompanied by changes in Nav1.6 pattern distribution at the axonal initial segment (AIS)
Summary
The serine/threonine kinase Akt (protein kinase B (PKB)) is a ubiquitously expressed enzyme that plays essential roles in cell growth, survival, motility, and regulation of metabolism, and homeostasis in almost all organs including, the brain [1,2,3,4,5,6,7,8,9]. Pertinent to its function as a prominent signaling molecule, inactive Akt is located in the cytosol and is recruited to the plasma membrane upon the activation of transmembrane receptors, such as tyrosine kinases receptors (TYK-R) and G-protein coupled receptors (GPCR) through phosphatidylinositol-3,4,5-trisphosphate (PIP3) [12,13,14,15,16,17,18]. Given the diverse downstream regulatory effects of Akt upon TYK-R and GPCR activation, it is unsurprising that Akt is involved in virtually all cellular functions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
