Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Abstract

Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Nav1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation.

Inhibition of the Akt/PKB Kinase Increases Nav1.6-Mediated Currents and Neuronal Excitability in CA1 Hippocampal Pyramidal Neurons

“…As described by Milescu et al [55], a depolarizing pre-pulse step was used to inactivate Na v channels distant from the recording electrode, and a second step was applied shortly afterward to record the Na v channels close to the recording pipette (Figure 2A), similar to our previous publication [56]. Importantly, hippocampal CA1 pyramidal neurons represent a promising cellular target to be affected by changes in Akt signaling, as these cells abundantly express Na v 1.6 channels where they contribute to somatic I Na and intrinsic excitability, Na v 1.6 channels are abundantly expressed in hippocampal CA1 pyramidal neurons, where they contribute to somatic I Na and intrinsic excitability [57][58][59][60]. 2.…”

Effective Accentuation of Voltage-Gated Sodium Current Caused by Apocynin (4′-Hydroxy-3′-methoxyacetophenone), a Known NADPH-Oxidase Inhibitor

“…Pyrethroids (e.g., permethrin and cypermethrin), known to activate I Na , have also been reported to disrupt NOX activity in brain tissue (striatum) [ 49 ]. Therefore, through ionic mechanisms shown herein, pyrethroids or other structurally similar compounds are able to adjust the functional activities of varying types of neuroendocrine or endocrine cells, or heart cells, if similar in vivo results exist [ 6 , 7 , 11 , 12 , 13 , 50 ]. To this end, the overall findings from our study highlight an important alternative aspect that has to be taken into account, inasmuch as there is the beneficial or ameliorating effect of aPO in various pathologic disorders, such as inflammatory or neurodegenerative diseases, and heart failure [ 1 , 3 , 6 , 7 , 9 , 10 , 11 , 12 , 13 , 16 , 42 ].…”

The Na+/Ca2+ Exchanger 3 Is Functionally Coupled With the NaV1.6 Voltage-Gated Channel and Promotes an Endoplasmic Reticulum Ca2+ Refilling in a Transgenic Model of Alzheimer’s Disease

“…In the present study, we have found that the I Na mediated by the Na V 1.6 channel not only are crucial players in neuronal hyperexcitability ( Patel et al, 2016 ; Wang et al, 2016 ; Ciccone et al, 2019 ; Zybura et al, 2021 ), but also modulate [Ca 2+ ] i by inducing the activation of the NCX reverse activity thus providing a Ca 2+ source from the extracellular space to refill the ER Ca 2+ stores. This evidence sheds new light on the Na V 1.6 upregulation in AD neurons and suggests that its downstream effects may also depend on channel sub-cellular localization as well as on Na V 1.6 interacting proteins.…”