The voltage-gated Na+ channel was first cloned by Noda et al. (1984). Specifically, they sequenced the cDNA for the Electrophorus electricuselectroplax sodium channel, identified four repeated homology domains, and within each unit they identified clustered regions of positively charged amino acids. Now, it is well established that the four repeated homology domains form the voltage-gated Na+-selective aqueous ion channel pore (Wood et al., 2004). Each of these domains (I–IV) has six transmembrane segments (S1-S6) (Cestèle and Catterall, 2000). The positively charged S4 segment is the voltage sensor, whose outward movement at positive membrane potentials exerts force on the S5-S6 linker, thus opening the ion channel (Yarov-Yarovoy et al., 2012).
The channels open within the order of a millisecond and their ionic current is also eliminated within a millisecond (Cummins, Sheets, Waxman, 2007). The short intracellular loop connecting domains III and IV is involved in channel inactivation (Cestèle and Catterall, 2000). The four homologous domains collectively form the ? subunit of the voltage-gated Na+ channels (Wood et al.
, 2004). Voltage-gated Na+ channels themselves are a family of nine structurally related ? subunits (Wood et al., 2004; see Table 1). These nine ? subunits differ in terms of cellular and tissue expression, subcellular expression, and differential expression profiles during development (Yu and Catterall, 2003).
The ? subunits can interact with accessory single-transmembrane ? subunits that may be influencing the localization and/or membrane stabilization of the ? subunits (Cummins, Sheets, Waxman, 2007). Voltage-gated Na+ channels are widely known for their role in the initiation and propagation of action potentials. However, in the field of pain, their functions extend beyond that of action potential initiation and propagation, as they are involved significantly in development and mechanisms of chronic pain, given that mutations in Nav1.7 channels result in inherited erythromelalgia and paroxysmal extreme pain disorder (Cummins, Sheets, Waxman, 2007).
The structure of the voltage-gated Na+ channels can be seen under Fig. 1.