Abstract
Voltage-gated sodium channels (Nav) are responsible for the initiation and propagation of action potentials in excitable cells. From pain to heartbeat, these integral membrane proteins are the ignition stations for every sensation and action in human bodies. They are large (>200 kDa, 24 transmembrane helices) multi-domain proteins that couple changes in membrane voltage to the gating cycle of the sodium-selective pore. Nav mutations lead to a multitude of diseases - including chronic pain, cardiac arrhythmia, muscle illnesses, and seizure disorders - and a wide variety of currently used therapeutics block Nav. Despite this, the mechanisms of action of Nav blocking drugs are only modestly understood at this time and many questions remain to be answered regarding their state- and voltage-dependence, as well as the role of the hydrophobic membrane access pathways, or fenestrations, in drug ingress or egress. Nav fenestrations, which are pathways that connect the plasma membrane to the central cavity in the pore domain, were discovered through functional studies more than 40 years ago and once thought to be simple pathways. A variety of recent genetic, structural, and pharmacological data, however, shows that these fenestrations are actually key functional regions of Nav that modulate drug binding, lipid binding, and influence gating behaviors. We discovered that some of the disease mutations that cause arrhythmias alter amino acid residues that line the fenestrations of Nav1.5. This indicates that fenestrations may play a critical role in channel’s gating, and that individual genetic variation may also influence drug access through the fenestrations for resting/inactivated state block. In this review, we will discuss the channelopathies associated with these fenestrations, which we collectively name “Fenestropathy,” and how changes in the fenestrations associated with the opening of the intracellular gate could modulate the state-dependent ingress and egress of drugs binding in the central cavity of voltage gated sodium channels.
Highlights
Voltage-gated sodium channels (Nav) are the main triggers and propagators of action potentials (Catterall et al, 2020). These proteins were discovered in the 1950s by Hodgkin and Huxley and have since been studied by a variety of techniques, including cloning, overexpression/purification, electrophysiology, pharmacology, and structural biology. These studies have revealed the modular nature of the Nav protein with each channel consisting of a voltage-sensing domain (VSD), linker region (S4–S5 linker), inactivation particle (IFM), and sodium-selective pore domain (PD) that work in Fenestropathy of Sodium Channels concert to couple changes in membrane voltage to changes in membrane flux of sodium (Figures 1A,B)
These hydrophobic pathways, which connect the lipid phase of the plasma membrane to the hydrophilic central cavity, are not known to be important in voltagesensing, gating, or coupling and their role in normal channel function remains unknown, though they have been shown to play a role in drug binding to the PD (Hille, 1977; Gamal ElDin et al, 2018b)
About 80% of the missense mutations in Nav1.5 lead to either Long QT syndrome (LQT3) or Brugada syndrome (BRGDA1). Most of these missense mutations are in the classical regions of the channel, though we discovered some that occur in the four fenestrations of the channel (Tables 1, 2) (Figure 4) - which was surprising due to unknown function of these regions
Summary
Voltage-gated sodium channels (Nav) are the main triggers and propagators of action potentials (Catterall et al, 2020). These proteins were discovered in the 1950s by Hodgkin and Huxley and have since been studied by a variety of techniques, including cloning, overexpression/purification, electrophysiology, pharmacology, and structural biology. These studies have revealed the modular nature of the Nav protein with each channel consisting of a voltage-sensing domain (VSD), linker region (S4–S5 linker), inactivation particle (IFM), and sodium-selective pore domain (PD) that work in
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.
