Table 1.
Summary of the different types of VGSC, and the channelopathies associated to mutations in the genes encoding the α subunits.
| Gene | Chromosome | Channel | Expression | TTX | EC50 | Human channelopathies |
|---|---|---|---|---|---|---|
| SCN1A | 2q24.3 | NaV1.1 | Cell bodies of central neurons (“Brain type I”), T-tubules in myocytes (Brette and Orchard, 2006) | S | 6 nM (Clare et al., 2000) | Epilepsy and epileptic disorders, including febrile epilepsy and GEFS+ (generalized epilepsy with febrile seizure) (Escayg et al., 2000; Spampanato et al., 2001), Dravet syndrome [severe myoclonic epilepsy of infancy (SMEI)], Doose syndrome (myoclonic astatic epilepsy), intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms (West syndrome), Rasmussen’s encephalitis, and Lennox–Gastaut syndrome Non-epileptic disorders: familial hemiplegic migraine (FHM), familial autism, Panayiotopoulos syndrome (Lossin, 2009) |
| SCN2A | 2q24.3 | NaV1.2 | Central neurons (“Brain type II”), mainly localized to unmyelinated and premyelinated axons | S | 12 nM (Noda et al., 1986) | Inherited febrile seizures and epilepsy (Sugawara et al., 2001) |
| SCN3A | 2q24.3 | NaV1.3 | Cell bodies of central neurons (primarily expressed in embryonic/early prenatal life), cardiac myocytes | S | 4 nM (Meadows et al., 2002) | Potential contributor to peripheral neuropathic pain after spinal cord injury (Hains et al., 2003) |
| SCN4A | 11 (human), 17q23.3 (mouse) | NaV1.4 | Skeletal muscle (high levels in adult muscle, low levels in neonatal muscle) | S (non-selective) | 5 nM (rat; Trimmer et al., 1989), 25 nM (human; Chahine et al., 1994) | Muscle sodium channelopathies (hyperkalemic periodic paralysis, paramyotonia congenital, and potassium-aggravated myotonia, myasthenic syndrome, hypokalemic periodic paralysis type 2, malignant hyperthermia susceptibility; Cannon, 1997) |
| SCN5A | 3p21–24 | NaV1.5 | Cardiac myocytes, immature and denervated skeletal muscle, certain brain neurons | R | 2–6 μM (Goldin, 2001) | Cardiac sodium channelopathies: Congenital long QT syndrome (Wang et al., 1995; Chen et al., 1998), Idiopathic ventricular fibrillation (Brugada syndrome; Chen et al., 1998; Akai et al., 2000), Isolated cardiac conduction system disease, atrial standstill, congenital sick sinus syndrome, sudden infant death syndrome, dilated cardiomyopathy, other conduction disorders and arrhythmias (George, 2005) |
| SCN8A | 15 (human), 12q13 (mouse) | NaV1.6 | Somatodendritic distribution in output neurons of cerebellum, cerebral cortex, hippocampus; Purkinje cells in cerebellar granule cell layer; astrocytes, and Schwann cells; DRG; nodes of Ranvier in PNS and CNS; T-tubules in cardiac myocytes | S (non-selective) | 1 nM (rat; Dietrich et al., 1998), 6 nM (mouse; Smith et al., 1998) | Cerebellar ataxia in jolting mice (Kohrman et al., 1996); motor end-plate disease in mice (Burgess et al., 1995) |
| SCN9A | 2q24 | NaV1.7 | All types of DRG neurons, sympathetic neurons, Schwann cells, neuroendocrine cells | S (non-selective) | 4 nM (rat), 25 nM (human; Catterall et al., 2005) | Congenital insensitivity to pain (CIP), familial primary erythromelalgia, and paroxysmal extreme pain disorder (PEPD; Lampert et al., 2010) |
| SCN10A | 3p22.2 | NaV1.8 | DRG neurons, human heart (Facer et al., 2011; Yang et al., 2012), and intracardiac neurons (Verkerk et al., 2012) | R | 60 mM (Catterall et al., 2005) | Peripheral pain syndromes; the channel is up regulated in some models of inflammatory pain; alterations in PR interval and ventricular conduction in the heart (Chambers et al., 2010; Sotoodehnia et al., 2010). |
| SCN11A | 3p22.2 | NaV1.9 | c-type neurons in DRG (nociception) | R | 40 mM (Catterall et al., 2005) | Potential role in nociception and hyperalgesic syndromes |
| SCN7A | 2q24.3 | NaX | DRG neurons; neurons of hippocampus, thalamus, and cerebellum, median preoptic nucleus, but mainly in the circunventricular organs (CVO); PNS; heart; skeletal muscle; uterus | Unknown | – | Potential role in temporal lobe epilepsy (Gorter et al., 2010); the lack of NaX in neurons from CVO would affect the ability to control body fluids and ionic balance (Hiyama et al., 2002; Noda, 2006) |
S, sensitive; R, resistant; CNS, central nervous system; PNS, peripheral nervous system; DRG, dorsal root ganglia.