Sodium channels

Sodium channels are ion channels that have a largely selective conductivity for sodium ions. Sodium channels can be activated voltage-dependent (so-called voltage-controlled sodium channels) or ligand-controlled, analogous to other ion channels(calcium channels; potassium channels). In the CNS, PNS and muscles, neurotransmitters such as acetylcholine, serotonin and glutamate, but also ATP and cyclic AMP (cAMP) act as ligands for certain selective sodium channels.

Voltage dependent sodium channels: These are transmembrane, pore-forming glycoproteins in cell membranes. They consist of two different subunits: the so-called alpha-subunit with a mass of about 230-260 kDa and associated beta-subunits with a mass of about 36 kDa (Catterall WA 2012). The alpha subunit is the structure-forming subunit (the actual pore is formed in it). Its switching behaviour is modulated by the beta subunits. The beta subunit is formed from four homologous domains linked by covalent bonds.

Currently, nine different subtypes of voltage-activated sodium channels are known. They are called Nav1.1 to Nav1.9. Here the index v stands for "voltage-activated". The first digit identifies the gene family (so far only one gene family is known), the second digit stands for the coding gene (1 to 9, arranged in the order of discovery). Voltage-activated sodium channels are expressed in electrically excitable cells. There, their function is to generate action potentials (Goldin AL 2001). In electrically excitable tissues such as heart or skeletal muscles, Na+ channels are indispensable for the transmission of excitation. In addition, Na+ channels are also found on electrically non-excitable cells such as astrocytes, fibroblasts and various tumour cells. In these cells they influence essential processes such as phagocytosis, motility and the activity of the Na+-K+ pump (Black JA et al. 2013).

The subtypes Nav1.1, Nav1.2 and Nav1.3 are mainly found in the central nervous system (CNS). The isoform Nav1.4 is the dominant subtype in skeletal muscles, the subtype Nav1.5 that of the myocardium and the isoforms Nav1.6, Nav1.7, Nav1.8 and Nav1.9 that of the peripheral nervous system (PNS) (Blechschmidt S et al. (2008). The individual subtypes differ e.g. in their electrophysiological properties. They also differ in their sensitivity to certain toxins and drugs.

Activation: When a stimulus triggers an action potential, the depolarisation of the membrane opens the "activation gate". Na+ ions can flow in. A rapid inactivation follows (1 to 2 milliseconds). The "Inactivation gate" is blocked (see figure). In this state the channels cannot be reactivated for a certain time. In this non-activatable state of the channel no further sodium ions can pass through. The channels reach the activatable state (activation gate closed and inactivation gate open) again after a repolarization of the membrane (by K+ current). Besides the fast activation there is also a slow inactivation. Possibly this leads to a collapse of the pore.

Non-voltage-activated sodium channels: An example of a non-voltage-activated sodium channel is the epithelial sodium channel (ENaC = epithelial Na channel; also SCNN1 of sodium channel non-neuronal 1 or ASSC of amiloride sensitive sodium channel), a membrane-bound ion channel which is permeable to Li+ ions and protons, but especially to Na+ ions. This type of channel is open in its basic state (so-called constitutively active channel). The ENaC consists of three subunits (α, β, γ), which are probably constituted to a heterotrimer. Each of the three subunits has two transmembrane helices and an extracellular loop. The amino and carboxy termini of the polypeptide chains are each located in the cytosol.

Occurrence: ENaCs are located in the apical membranes of polar epithelial cells, mainly in the kidney, lung and colon. They are responsible for the transepithelial transport of Na+ ions and thus play an important role in maintaining Na+ and K+ concentrations in blood, epithelia and intercellular space. ENaC activity and expression in kidney and colon is modulated by the mineralocorticoid aldosterone . Furthermore, the ENaC channel type is found in gustatory cells and plays an important role in the perception of salty taste.

Ligand-controlled Na+ channels: Ligand-controlled Na+ channels represent another group of Na+ channels. These are opened and closed when a ligand is bound. Ligand-controlled Na+ channels belong to different protein families. In the CNS, PNS and muscles, neurotransmitters such as acetylcholine, serotonin and glutamate, but also ATP and cyclic AMP (cAMP) act as ligands.

Mutations in the sodium channels

Mutations in genes for Na+ channel proteins lead to different "channel" diseases (so-called channelelopathies) - depending on the expression pattern and the functional change resulting from the mutation, e.g. change in voltage dependence or disturbance of fast and slow inactivation. Mutations that lead to complete loss of function are much rarer (Catterall WA 2012). Channelelopathies always manifest where the affected Na+ receptor preferentially occurs:

• Mutations in the gene for the Nav1.4 lead to muscular diseases. Periodic paralyses are characterized by episodically occurring attacks of muscle weakness.
• Paramyotonia congenita is characterized by cold-induced muscle stiffness and weakness. In both cases, the mutations lead to increased channel activity by disturbing rapid and/or slow inactivation (George AL 2005). The duration of the muscular action potentials is prolonged, which in turn disturbs the K+ transport.
• Mutations in the Nav1.5 gene lead to severe and sometimes life-threatening cardiac rhythm and stimulus conduction disorders.
• Long QT syndrome type III: In patients with long QT syndrome type III, a disturbed inactivation of this channel leads to prolonged action potentials.
• Brugada syndrome: Mutations that cause an excitation conduction disorder (Brugada syndrome) reduce the maximum possible Na+ input by an increased tendency of the channels to slow inactivation (Remme CA et al. (2014).
• Epilepsy: Mutations in the genes for Nav1.1 and Nav.1.2 as well as for the β1 subunit of the Na+ channels can trigger epilepsy disorders of varying severity (Note: More than 100 different mutations have been detected in the gene for Nav1.1).
• Generalized epilepsy with febrile convulsions: In benign generalized epilepsy with febrile convulsions plus (GEFS+), febrile attacks occur in early childhood. The episodes of epilepsy which occur later have a variable phenotype.
• Dravet syndrome: In Dravet syndrome (Severe myoclonic epilepsy of infancy) psychomotor development is usually severely impaired.
• Familial hemiplegic migraine
• Erythromelalgia: Mutations in the gene for Nav1.7 lead to pain disorders. In erythromelalgia (vascular disease with redness, pain and temperature increase of the skin) the tension dependence of the channel is altered.
• Paroxysmal extreme pain disorder: In paroxysmal extreme pain disorder, mutations in the gene for Nav1.7 lead to a disorder in the inactivation of the channel. A lack of functional channels leads to a complete loss of pain sensation (Congenital indifference of pain) (Remme CA et al. 2014)

Drugs (examples) with voltage-controlled Na+ channels as target structures:

• Local anaesthetics: Lidocaine, procaine: binding to open channels, modulation of action potentials; pain elimination during surgery
• Antiepileptic drugs: phenytoin, lamotrigine, carbamazepine1, valproate, topiramate: binding to inactivated channels; stabilisation of the inactive state; prevention of the generation of rapidly successive action potentials; use in various forms of epilepsy
• Antiarrhythmics: binding to open channels Modulation of action potentials
  • Class IA: Quinidine, procainamide, disopyramide: inhibition of the rapid Na+ influx Prolongation of the action potential Prolongation of the refractory period. Indication: ventricular arrhythmias
  • Class IB: Lidocaine, Phenytoin, Aprindin: Shortening of the action potential Shortening of the refractory period. Indication: ventricular tachycardia
  • Class IC: flecainide, propafenone: inhibition of the rapid Na+ influx no effect on the duration of the action potential. Indication: (supra-)ventricular tachycardia, paroxysmal atrial fibrillation

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