The hitchhiker’s guide to the voltage-gated sodium channel galaxy

Abstract

Eukaryotic voltage-gated sodium (Nav) channels contribute to the rising phase of action potentials and served as an early muse for biophysicists laying the foundation for our current understanding of electrical signaling. Given their central role in electrical excitability, it is not surprising that (a) inherited mutations in genes encoding for Nav channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Nav channels are targeted by various drugs and naturally occurring toxins. Although the overall architecture and behavior of these channels are likely to be similar to the more well-studied voltage-gated potassium channels, eukaryotic Nav channels lack structural and functional symmetry, a notable difference that has implications for gating and selectivity. Activation of voltage-sensing modules of the first three domains in Nav channels is sufficient to open the channel pore, whereas movement of the domain IV voltage sensor is correlated with inactivation. Also, structure–function studies of eukaryotic Nav channels show that a set of amino acids in the selectivity filter, referred to as DEKA locus, is essential for Na+ selectivity. Structures of prokaryotic Nav channels have also shed new light on mechanisms of drug block. These structures exhibit lateral fenestrations that are large enough to allow drugs or lipophilic molecules to gain access into the inner vestibule, suggesting that this might be the passage for drug entry into a closed channel. In this Review, we will synthesize our current understanding of Nav channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Nav channels that, for the time being, serve as structural models of their eukaryotic counterparts.

Pharmacology of the Na v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

“…These effects can account for the observed toxin-dependent increase in peak Na + current in cells heterologously expressing Na v 1.1, as well as the increased action potential firing rate in mechanosensitive primary afferent fibers (10). These properties are similar to those described for other toxins from arachnids that interact with the S3b-S4 motif in VSDIV (1).…”

“…Discussion Na v channel inactivation is a complex process consisting of fast and slow components that may involve a contribution from one or more voltage sensor domains (1,13,15,16,19). Understanding these processes and elucidating strategies for their pharmacologic modulation may aid drug discovery efforts aimed at treating Na v 1.1-associated disorders, such as epilepsy, migraine, and mechanical pain (2, 3, 5-8, 10, 11).…”

“…Among the most robust loci for regulating excitability are voltage-gated sodium (Na v ) channels, a protein family consisting of nine subtypes (Na v 1.1-1.9) that initiate and propagate action potentials throughout the human body (1). Loss-of-function mutations in Na v 1.1 produce epilepsy syndromes, likely reflecting the critical importance of this Na v channel subtype in controlling the excitability of inhibitory interneurons in the brain (2)(3)(4).…”

“…However, Na v channel inactivation is a complex process that includes binding of an inactivation particle to the intracellular side of the pore (fast inactivation), as well as a structurally and temporally distinct process whereby the selectivity filter becomes nonconducting after prolonged depolarization (slow inactivation) (1,13,14). Mammalian Na v channels are large proteins composed of four homologous domains that form a pseudo-fourfold symmetric channel comprising a central pore surrounded by four voltage sensors, one from each domain (1).…”

“…Mammalian Na v channels are large proteins composed of four homologous domains that form a pseudo-fourfold symmetric channel comprising a central pore surrounded by four voltage sensors, one from each domain (1). Accumulating evidence suggests that activation gate opening is associated with movement of voltage sensors in domains I-III (VSDI-III), whereas fast inactivation is initiated by subsequent movement of the voltage sensor in domain IV (VSDIV) (1,15,16); however, the role of VSDIV in slow inactivation and the possibility of functional coupling between fast and slow inactivation remain matters of debate (17)(18)(19).…”