Eukaryotic voltage-gated sodium (Na_v) 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 Na_v channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Na_v 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 Na_v 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 Na_v 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 Na_v 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 Na_v 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 Na_v channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Na_v channels that, for the time being, serve as structural models of their eukaryotic counterparts.

Voltage-gated sodium (Na_v) channels initiate action potentials in most neurons, including primary afferent nerve fibres of the pain pathway. Local anaesthetics block pain through non-specific actions at all Na_v channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes of these channels and their contributions to chemical, mechanical, or thermal pain. Here we identify and characterize spider (Heteroscodra maculata) toxins that selectively activate the Na_v1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Na_v1.1-expressing fibres are modality-specific nociceptors: their activation elicits robust pain behaviours without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibres also express Na_v1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Na_v1.1 channels in regulating the excitability of sensory nerve fibres that mediate mechanical pain.

Voltage-activated sodium (Na_v) channels are crucial for the generation and propagation of nerve impulses, and as such are widely targeted by toxins and drugs. The four voltage sensors in Na_v channels have distinct amino acid sequences, raising fundamental questions about their relative contributions to the function and pharmacology of the channel. Here we use four-fold symmetric voltage-activated potassium (K_v) channels as reporters to examine the contributions of individual S3b–S4 paddle motifs within Na_v channel voltage sensors to the kinetics of voltage sensor activation and to forming toxin receptors. Our results uncover binding sites for toxins from tarantula and scorpion venom on each of the four paddle motifs in Na_v channels, and reveal how paddle-specific interactions can be used to reshape Na_v channel activity. One paddle motif is unique in that it slows voltage sensor activation, and toxins selectively targeting this motif impede Na_v channel inactivation. This reporter approach and the principles that emerge will be useful in developing new drugs for treating pain and Na_v channelopathies.

How activation leads to gating: Voltage-gated sodium (Na _v ) channels are key players in electrical signaling. Central to their function is fast inactivation, and mutants that impede this cause conditions such as epilepsy and pain syndromes. The channels have four voltage-sensing domains (VSDs), with VSD4 playing an important role in fast inactivation. Clairfeuille et al. determined the structures of a chimera in which VSD4 of the cockroach channel Na _v PaS is replaced with VSD4 from human Na _v 1.7, both in the apo state and bound to a scorpion toxin that impedes fast activation (see the Perspective by Chowdhury and Chanda). The toxin traps VSD4 in a deactivated state. Comparison with the apo structure shows how interactions between VSD4 and the carboxyl-terminal region change as VSD4 activates and suggests how this would lead to fast inactivation. Science , this issue p. eaav8573 ; see also p. 1278