Voltage-gated sodium channels NaV1.4–NaV1.8 (NaV1.4–NaV1.8)

Voltage-gated sodium channels (NaV) are critical membrane proteins that mediate the rapid influx of sodium ions, essential for the initiation and propagation of action potentials in excitable tissues (Catterall, 2000). The group NaV1.4 through NaV1.8 represents a diverse set of isoforms with specialized physiological roles: NaV1.4 (SCN4A) is the primary channel in skeletal muscle, NaV1.5 (SCN5A) is the dominant isoform in cardiac myocytes, and NaV1.6 (SCN8A) is widely expressed in the central and peripheral nervous systems (de Lera Ruiz and Kraus, 2015). NaV1.7 (SCN9A) and NaV1.8 (SCN10A) are predominantly localized in peripheral sensory neurons, where they play pivotal roles in nociceptive signaling and pain perception (Waxman, 2023). These channels are major therapeutic targets for conditions ranging from cardiac arrhythmias and skeletal muscle myotonias to chronic and acute pain (Sharan et al., 2015). While non-selective blockers like lidocaine and mexiletine are used clinically, the development of subtype-selective inhibitors—particularly for NaV1.7 and NaV1.8—is a high-priority area for creating non-opioid analgesics with reduced side effects (Zou et al., 2024). However, the high structural homology between isoforms presents a significant challenge, as off-target inhibition of NaV1.5 can lead to life-threatening cardiotoxicity, and inhibition of NaV1.4 can cause muscle weakness (Peschel et al., 2020).

Other names

SCN4A-SCN10AVGSC 1.4-1.8Sodium channel protein type 4 to type 10 subunit alphaVoltage-gated sodium channel alpha subunits 4-10

Inhibition of sodium ion conductance by binding to the alpha subunit pore or voltage-sensing domains, thereby stabilizing the inactivated state and reducing cellular excitability.