Voltage-gated sodium channel alpha subunit (Nav1.5, Nav1.7, Nav1.8, Nav1.9) (Nav1.5, Nav1.7, Nav1.8, Nav1.9)

Voltage-gated sodium channels (Nav) are transmembrane proteins that allow the rapid influx of sodium ions, a process fundamental to the initiation and propagation of action potentials in excitable cells [1, 2]. This specific group includes Nav1.5 (SCN5A), which is the primary isoform in the heart and is essential for maintaining normal cardiac rhythm and conduction [1, 4]. It also includes Nav1.7 (SCN9A), Nav1.8 (SCN10A), and Nav1.9 (SCN11A), which are predominantly expressed in the peripheral nervous system and serve as critical regulators of pain signaling [3, 6]. Mutations in Nav1.5 are associated with cardiac conditions such as Brugada syndrome and Long QT syndrome type 3, while mutations in the peripheral isoforms are linked to various pain disorders, including erythromelalgia and congenital insensitivity to pain [4, 5]. Pharmacological agents targeting these channels include local anesthetics, antiarrhythmics, and novel selective inhibitors like Suzetrigine (VX-548), which aim to reduce hyperexcitability by blocking the ion pore or stabilizing the inactivated state [3, 5]. A significant challenge in drug development is achieving high selectivity for pain-related isoforms (Nav1.7–1.9) over the cardiac Nav1.5 isoform to avoid life-threatening cardiotoxicity [3, 4]. References: [1] UniProt (P35498, Q15858, Q9Y5Y9, Q9UI33); [2] StatPearls, 'Physiology, Sodium Channels' (2023); [3] Dib-Hajj et al., Nature Reviews Neuroscience (2013); [4] Wilde & Amin, Circulation Research (2018); [5] Vertex Pharmaceuticals, Press Release (2024); [6] Bennett et al., Pain (2019).

Other names

Sodium channel protein type 5 subunit alphaSodium channel protein type 9 subunit alphaSodium channel protein type 10 subunit alphaSodium channel protein type 11 subunit alphaSCN5ASCN9ASCN10ASCN11AVoltage-gated sodium channel alpha subunitVGSC

These channels are targeted by drugs that act as pore blockers or allosteric modulators, which stabilize the channel in its non-conducting inactivated state to reduce cellular hyperexcitability [2, 5].