Passage of sodium between the cells and the extracellular medium
The exchanges of sodium between the cell and the external medium are done through protein structures: sodium enters the cell by voltage-dependant and receptor-dependant channels, exchangers, cotransporters; it leaves the cell via the Na+/K+ -ATPase pump.
Voltage-gated sodium channels
Voltage-gated sodium channels are formed of a polypeptide glycoprotein chain containing four transmembrane subunits with tryptophan residues. In spite of a common basic structure, there are differences between the sodium channels of various tissues.
These sodium channels are also permeable to cations other than sodium but, because of its very high concentration in the extracellular medium, Na + plays the essential part. The duration of opening of a channel is about one millisecond, time sufficient for the entry into a cell of 6 000 sodium ions.
Their opening is linked to depolarization. The probability for a sodium channel to be open depends on the potential: when the potential difference is of - 40 mV, the channel is closed; when the potential difference is null, the channel has a one in two chance to be open and when the potential difference reaches + 40 mV, the channel is open. They close again in spite of the maintenance of depolarization and pass into a state known as unactivated. Their activity can be modulated by phosphorylation of the intracellular part under the influence, for example, of the protein kinase A.
Disturbances of the voltage-gated sodium channels can induce disorders such as dysesthesias and paresthesias, either drug-induced or not.
A certain number of compounds inhibit the opening of voltage-dependant sodium channels:
- poisons like tetrodotoxin which, by its positively charged guanidine under usual conditions of pH, blocks the entry of the channel,
- drugs: local anesthetics, antiepileptics and class I antiarrhythmics
Receptor-dependant sodium channels
The three principal examples of receptor-dependant sodium channels are the nicotinic receptors present at the neuromuscular junction , synapses of the autonomic and of the central nervous system , NMDA glutamate receptors (See Acid glutamic, excitatory) and 5HT3 serotonin receptors (See Directly acting serotoninomimetics).
Secondary active transport
Exchangers and cotransporters use the ion gradient of concentration created by the Na+/K+ -ATPase pump for transfering ions and molecules between cells and the extracellular compartment.
Exchangers
The two principal exchangers are the sodium-calcium exchanger, Na+/ Ca2+ , and the sodium-proton exchanger, Na+/ H+ .
- Na+/ Ca2+ exchanger: the Na+/ Ca2+ exchanger of the plasma membrane is a bidirectional ion transporter that couples the translocation of sodium in one direction with that of calcium in the opposite direction. At the cardiac level, it causes the efflux of one Ca 2 + ion against the influx of three Na+ ions and inversely, i.e. when the intracellular concentration of Na+rises, it causes efflux of Na+and influx of Ca2+. This exchanger is present in other tissues smooth muscles, neurons, the external segment of cones (retina) where the stoechiometry of the exchange can be different from that of the heart.
- Na+/ H+ exchanger: it ensures an electroneutral exchange: influx of one ion Na + in the cell and efflux of one proton. It regulates intracellular pH by decreasing acidification. Amiloride, in large doses, inhibits it. The Na+/ H+ exchanger has an important role in the myocardium because, during ischemia the intracellular pH decreases; and during reperfusion, it increases by activation of Na+/H+ exchanger. This activation increases the influx of Na+ into the cell, which triggers secondarily the Na+/ Ca2+ exchanger which extrudes sodium and enters calcium, this last being able to cause cellular damage. Pharmacological attempts to inhibit the Na+/ H+ exchanger by amiloride in large doses were made.
Sodium cotransporters
The cotransporters Na+/amino acid, Na+/glucose, Na+/Cl-, Na+/K+ -2Cl-, Na+/transmitters allow entry into the cell of various molecules necessary to its functions.
Ultimately, it is the Na+ gradient between the extra and intracellular milieu created by Na+/K+ -ATPase pump which makes it possible for Na+ to have so much biological importance.
Primary active transport: Na+/K+-ATPASE
The efflux of sodium out of the cell is achieved by the Na+/K+ -ATPase pump. It extrudes three sodium ions and enters two potassium ions; it is an electrogenic pump causing cellular polarization, i.e. the creation of a potential difference between the interior of the cell and the extracellular medium.
The pump functions using the energy of ATP synthesized by mitochondrias during cellular respiration. This pump is inhibited by digoxin, which induces a rise in the intracellular sodium concentration and the activation of Na+/ Ca2+ exchange, inducing a calcium influx ( See “Inhibition of Na+/K+ -ATPASE: cardiac glycosides”. ).
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