Exciting channel Nav1.6

Today is SCN8A Awareness Day, and I thought it’s a good opportunity to take a deeper look at SCN8A channel and find out what makes it so special that it has its own awareness day.

So, the SCN8A gene encodes Nav1.6 channel, a member of the voltage-gated sodium channel family comprising nine isoforms: Nav1.1-Nav1.9. In excitable cells, such as neurons, voltage-gated sodium channels are responsible for the rising phase of action potentials and thus play a key role in controlling neuronal excitability.

So, all these isoforms share many similarities, but also exhibit a number of differences, particularly in their biophysical properties and expression patterns. For example, Nav1.1-Nav1.3 are expressed primarily in the brain, whereas Nav1.7-Nav1.9 are predominantly localized in peripheral neurons, where they have been associated with pain transduction. In turn, Nav1.6 is widely expressed in both the central and peripheral nervous system, which somewhat contrasts with the relatively limited distribution of other Navs.

But not only are Nav channels differentially distributed in various cell types, they are also asymmetrically distributed across the cell membrane. Some channels are mainly present in the cell body (soma), while others are localized predominantly on dendrites or axons. Nav1.6 channels, for example, are localized with high density in the axon initial segment and nodes of Ranvier, where they play a dominant role in the initiation and propagation of action potentials. Their expression on the soma is 40 times less than on the axon.

Not bad, but there is something more interesting about Nav1.6.

It turns out that in addition to its preferential localization on axons, Nav1.6 also exhibits some unique biophysical properties. First, it is activated at more negative voltages than Nav1.1 or Nav1.2, which facilitates the generation of an action potential at a lower threshold. Second, it rapidly recovers from inactivation, which favors repetitive firing. And third, it exhibits large persistent and resurgent currents, causing neuronal hyperexcitability and promoting repetitive firing.

How do you like it? Apparently, Nav1.6 functions as an orchestra conductor. The conductor waves his baton, and the entire ion channel orchestra begins to play. And if the conductor is sick and tired, the orchestra will not start on time and will play quietly, sluggishly and out of tune. But if the conductor is nervous and overexcited, the orchestra will play too fast and too loud.

Unfortunately, given how important Nav1.6 is for initiation and propagation of action potentials, disfunction of this channel has been associated with some pathological conditions, such as severe epilepsy and developmental delay. To date, more than 150 epilepsy-related mutations have been identified in SCN8A gene, but only about 20 of them have been functionally characterized. Gain-of-function variants have been associated with neuronal hyperexcitability and epileptic seizures, whereas loss-of-function variants (causing reduced neuronal activity) are often associated with intellectual disability, autistic features, and movement disorders.

SCN8A epilepsy is now known to affect about 550 people worldwide, and there is currently no standard treatment for the disease. Sodium channel blockers are often prescribed in case of gain-of-function, but in most cases, seizure treatment for SCN8A disorders remains inadequate.

As of today, I am aware of two companies developing treatments for SCN8A epilepsy. Neurocrine Biosciences is currently conducting the KAYAK Phase 2 study of NBI-921352 (a potent and highly selective Nav1.6 inhibitor) as an adjunctive therapy in children and young adults living with SCN8A Developmental and Epileptic Encephalopathy. And also, Praxis Precision Medicines, Inc. announced plans to initiate in 2023 the PRAX-562 (a preferential inhibitor of persistent sodium current) Phase 2 study for the treatment of pediatric patients with developmental and epileptic encephalopathies.

Like many rare disorders, families and their drive to advance research offer the greatest hope for children with SCN8A epilepsy. A number of “SCN8A Awareness and Research Organizations” now raise awareness of SCN8A, fund scientists studying SCN8A, and support the families around the world. If you would like to support them, please visit their websites below.

SCN8A Awareness and Research Organizations: