الفهرس 
• Structure and function of VGSCOnly 14 pages are availabe for public view
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Abstract
VGSC play a critical role in electrical signaling in the nervous system and are responsible for the initiation and propagation of APs. VGSCs are composed of one -subunit, that forms the core of the channel and is responsible for voltage-dependent gating and ion permeation, and several auxiliary -subunits. Considering the essential role of VGSC in the generation of the upstroke of the neuronal AP, it is not surprising that their dysfunction can cause severe neurological disorders.
A growing body of experimental evidence indicates that abnormal expression or function of VGSCs might have a role in the pathophysiology of epilepsy. Epileptic syndromes linked to VGSC mutations range in severity from relatively mild disorders such as benign neonatal-infantile familial seizures, simple febrile seizures, and generalized epilepsy with febrile seizures plus (GEFS+) to the epileptic encephalopathy termed severe myoclonic epilepsy of infancy (SMEI), also known as Dravet’s syndrome.
There are many antiepileptic drugs that mediate their actions by suppressing sodium VGSC. These drugs include: phenytoin, carbamazepine, valproate, lamotrigine, topiramate, ethosuximide, riluzole and lacosamide.
While familial hemiplegic migraine (FHM) is usually associated with mutations in the Cav1.2 calcium channel, a rare type of FHM has been linked to a Q1489K mutation in the SCN1A gene, which encodes the α-subunit of Nav1.1. Recent evidence from controlled clinical trials suggests that sodium channel blocker like lamotrigine and carbamazepine can reduce aura and migraine attacks.
Adult dorsal root ganglion neurons express at least five VGSC subtypes (Nav1.1 and Nav1.6–Nav1.9). Nav1.7 has recently received intense interest in the pain field. Gain of-function mutations in this subtype cause two different episodic pain syndromes: inherited erythromelalgia and paroxysmal extreme pain disorder. VGSC blockers, including the AEDs carbamazepine, phenytoin, and lamotrigine, might be efficacious in the treatment of neuropathic pain associated with painful peripheral neuropathies, such as diabetic neuropathy. In fibromyalgia, Duloxetine blocks persistent late Nav1.7 Na+ currents preferentially, which may in part account for its analgesic action.
Cerebellar dysfunction in multiple sclerosis (MS) is a significant contributor to disability. There is a growing body of evidence which suggests that mis-tuning of Purkinje cells, due to expression of an abnormal repertoire of sodium channels, contributes to cerebellar deficits in MS. Importantly, therapy with sodium channel-blocking agents improved the functional outcome. Based on these encouraging observations, clinical trials of lamotrigine and phenytoin have been initiated treating patients with secondary and primary progressive MS.
BACE1 and presenilin (PS)/γ-secretase are primary proteolytic enzymes responsible for the generation of pathogenic amyloid β-peptides (Aβ) in Alzheimer’s disease. It has been found that β-subunits of the voltage-gated sodium channel (Na(v)βs) also undergo sequential proteolytic cleavages mediated by BACE1 and PS/γ-secretase. Hyperforin that was known of its anti-amyloidogenic properties, can reduce oxidative and inflammatory damage in vitro and in transgenic rodent models, is able to prevent amyloid- (A) induced neurotoxicity, so it was suggested to be utilized in treatment of Alzheimer’s disease. It is also possible that hyperforin increases [Na+]i through activation of amiloride sensitive sodium conductance pathways.
Five sodium channelopathies of skeletal muscle have been identified to date. All of them follow an autosomal dominant mode of transmission. Four of the disorders which are caused by similar NaV1.4 gain-of-function effects have distinct clinical features and therapies which may even be contrary despite common pathogenesis. Although the α subunit’s function is modulated by the β1 subunit, all mutations that cause a muscle disease are situated in NaV1.4.