*2.5. Voltage-Gated Na*<sup>+</sup> *Channels*

Voltage-gated Na<sup>+</sup> channels (Na*V*) are crucial not just for excitable cells like central or peripheral neurons, skeletal or cardiac muscle cells, but also occur in immune cells, which are considered non-excitable [151]. In excitable cells, the principal role of Na*<sup>V</sup>* channels is generating action potentials. Action potentials are generated, if a sufficient number of Na*<sup>V</sup>* channels are activated in response to a local depolarization. As opposed to local depolarizations which can only spread over a few millimeters, action potentials can travel along several meters and thus transfer the information to the central nervous system. The stronger a local depolarization is, for example in response to a noxious stimulus, the more action potentials are triggered [2]. If Na*<sup>V</sup>* channels are rendered non-functional, action potentials cannot be evoked and information transfer to the central nervous system is stopped [152–155]. This mechanism is highlighted by patients carrying loss-of-function mutations in their Na*V*1.7 or Na*V*1.9 genes, who experience insensitivity towards painful stimuli [156].

To date, nine pore-forming *α*-subunits of Na*<sup>V</sup>* channels are described, designated Na*V*1.1 to Na*V*1.9 [11]. Only Na*V*1.6 to Na*V*1.9 channels can be found in nociceptive neurons. A functional voltage-gated Na<sup>+</sup> channel is formed by a pore-forming *α*-subunit and one additional auxiliary *β*-subunit, of which four (*β*1 to *β*4) have been described. An *α*-subunit is composed of 24 transmembrane segments, which can be grouped into four domains (DI–DIV) of six transmembrane segments each (S1–S6) [151]. The transmembrane segments S1–S4 of each domain form the voltage-sensor, whereas all four S5 and S6 segments contribute to the channel pore. The S4 segments are of particular interest as they harbor a number of positively charged amino acid residues. These residues move the entire S4 segment upwards upon depolarization and lead to the gating of these ion channels. This basic principle of activation is conserved among all members of voltage-gated ion channels [157]. Voltage-gated Na<sup>+</sup> channels activate within a fraction of a millisecond and subsequently enter a fast-inactivated state. This inactivation is mediated by the intracellularly located DIII-DIV linker [151]. The subunits Na*V*1.5, Na*V*1.8 and Na*V*1.9 have a low affinity for tetrodotoxin (TTX) as it ranges from 10 to 100 μM. The affinity for all other subtypes ranges between 1 to 10 nM [11]. The former subtypes are therefore described as TTX-insensitive and this represents a simple experimental tool to distinguish between Na*V*s relevant for nociception and those that are not relevant for nociception [151]. In addition to the previously described channelopathies leading to pain-insensitive patients, the importance of voltage-gated Na<sup>+</sup> channels for nociception is highlighted by the fact that the most widely used local anesthetic drug, lidocaine, leads to a use-dependent block of these channels, which prevents the propagation of painful stimuli [151].
