Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na⁺) through a cell's plasma membrane. An Integral Membrane Protein ( IMP) is a Protein Molecule (or assembly of proteins that is permanently attached to the Biological membrane. Ion channels are pore-forming Proteins that help establish and control the small Voltage Gradient across the Plasma membrane of all living Sodium (ˈsoʊdiəm is an element which has the symbol Na( Latin natrium, from Arabic natrun) atomic number 11 atomic mass 22 The cell is the structural and functional unit of all known living Organisms It is the smallest unit of an organism that is classified as living and is often called The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer ^[1][2] They are classified according to the trigger that opens the channel for such ions, i. e. either a voltage-change (voltage-gated sodium channels) or binding of a substance (a ligand) to the channel (ligand-gated sodium channels). In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally

In excitable cells such as neurons, myocytes, and certain types of glia, sodium channels are responsible for the rising phase of action potentials. Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information Muscle (from Latin musculus, diminutive of mus "mouse" is contractile tissue of the body and is derived from the Glial cells, commonly called neuroglia or simply glia (Greek for "glue" are non- Neuronal cells that provide support and nutrition In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal

Voltage-gated

Structure

Diagram of a voltage-sensitive sodium channel α-subunit. G - glycosylation, P - phosphorylation, S - ion selectivity, I - inactivation, positive (+) charges in S4 are important for transmembrane voltage sensing. Glycosylation is the enzymatic process that links Saccharides to produce glycans, either free or attached to Proteins and Lipids This enzymatic Phosphorylation is the addition of a Phosphate (PO4 group to a Protein molecule or a small molecule ^[3]

Sodium channels can often be isolated from cells as a complex of two types of protein subunits, α and β. An α subunit forms the core of the channel. When the α subunit protein is expressed by a cell, it is able to form channels which conduct Na⁺ in a voltage-gated way, even if β subunits are not expressed. When β subunits assemble with α subunits the resulting complex can display altered voltage dependence and cellular localization.

The α-subunit has four repeat domains, labeled I through IV, each containing six membrane-spanning regions, labeled S1 through S6. The highly conserved S4 region acts as the channel's voltage sensor. Conservation refers to a high degree of similarity in orthologous DNA sequences protein sequences, or Protein structures amongst various The voltage sensitivity of this channel is due to positive amino acids located at every third position. When stimulated by a change in transmembrane voltage, this region moves toward the extracellular side of the cell membrane, allowing the channel to become permeable to ions. Membrane potential (or transmembrane potential) is the Voltage difference (or Electrical potential difference between the interior and exterior of a The ions are conducted through a pore, which can be broken into two regions. The more external (i. e. , more extracellular) portion of the pore is formed by the "P-loops" (the region between S5 and S6) of the four domains. This region is the most narrow part of the pore and is responsible for its ion selectivity. The inner portion (i. e. , more cytoplasmic) of the pore is formed by the combined S5 and S6 regions of the four domains. The region linking domains III and IV is also important for channel function. This region plugs the channel after prolonged activation, inactivating it.

Gating

Voltage-gated sodium channels have three types of states: deactivated (closed), activated (open), and inactivated (closed). Channels in the deactivated state are thought to be blocked on their intracellular side by an "activation gate", which is removed in response to stimulation that opens the channel. The ability to inactivate is thought to be due to a tethered plug (formed by domains III and IV of the alpha subunit), called an inactivation gate, that blocks the inside of the channel shortly after it has been activated. During an action potential the channel remains inactivated for a few milliseconds after depolarization. A millisecond (from Milli- and Second; abbreviation ms is one thousandth of a Second. The inactivation is removed when the membrane potential of the cell repolarizes following the falling phase of the action potential. This allows the channels to be activated again during the next action potential. Genetic diseases that alter sodium channel inactivation can cause muscle stiffness or epileptic seizures because of the introduction of a so-called window current, during which sodium channels are tonically active, causing muscle and/or nerve cells to become over-excited.

The temporal behaviour of sodium channels can be modeled by a Markovian scheme or by the Hodgkin-Huxley-type formalism. A hidden Markov model ( HMM) is a Statistical model in which the system being modeled is assumed to be a Markov process with unknown parameters and the The Hodgkin–Huxley model is a Scientific model that describes how Action potentials in Neurons are initiated and propagated In the former scheme, each channel occupies a distinct state with differential equations describing transitions between states; in the latter, the channels are treated as a population that are affected by three independent gating variables. A differential equation is a mathematical Equation for an unknown function of one or several variables that relates the values of the In Statistics, a statistical population is a set of entities concerning which Statistical inferences are to be drawn often based on a Random sample Each of these variables can attain a value between 1 (fully permeant to ions) and 0 (fully non-permeant), the product of these variables yielding the percentage of conducting channels.

Impermeability to other ions

The pore of sodium channels contains a selectivity filter made of negatively charged amino acid residues, which attract the positive Na⁺ ion and keep out negatively charged ions such as chloride. In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this The chloride Ion is formed when the element Chlorine picks up one Electron to form an Anion (negatively-charged ion Cl&minus The cations flow into a more constricted part of the pore that is 0. 3 by 0. 5 nm wide, which is just large enough to allow a single Na⁺ ion with a water molecule associated to pass through. A nanometre ( American spelling: nanometer, symbol nm) ( Greek: νάνος nanos dwarf; μετρώ metrό count) is a Water is a common Chemical substance that is essential for the survival of all known forms of Life. In Chemistry, a molecule is defined as a sufficiently stable electrically neutral group of at least two Atoms in a definite arrangement held together by The larger K⁺ ion cannot fit through this area. Differently sized ions also cannot interact as well with the negatively charged glutamic acid residues that line the pore. Glutamic acid (abbreviated as Glu or E) is one of the 20 Alpha Amino acids It is not among the human Essential amino acids Its

Diversity

Voltage-gated sodium channels normally consist of an alpha subunit which forms the ion conduction pore and one to two beta subunits which have several functions including modulation of channel gating. ^[4] Expression of the alpha subunit alone is sufficient to produce a functional channel.

Alpha subunits

Figure 1. Likely evolutionary relationship of the nine known human sodium channels.

The family of sodium channels has nine known members, with amino acid identity >50% in the transmembrane and extracellular loop regions. A standardized nomenclature for sodium channels is currently used and is maintained by the IUPHAR. The International Union of Basic and Clinical Pharmacology (IUPHAR is a voluntary non-profit association representing the interests of scientists in Pharmacology -related fields ^[5][6]

The proteins of these channels are named Na_v1. 1 through Na_v1. 9. The gene names are referred to as SCN1A through SCN11A (the SCN6/7A gene is part of the Na_x sub-family and has uncertain function). The likely evolutionary relationship between these channels, based on the similarity of their amino acid sequences, is shown in figure 1. The individual sodium channels are distinguished not only by differences in their sequence but also by their kinetics and expression profiles. Some of this data is summarized in table 1, below.

Beta subunits

In addition to regulating channel gating, sodium channel beta subunits also modulate channel expression and form links to the intracelluar cytoskeleton and extracellular matrix. The Nav19 voltage-gated Sodium ion channel protein is encoded by the gene. Sodium channel voltage-gated type VII alpha, also known as SCN7A, is a human Gene. Not to be confused with Intercellular, meaning "between cells" cytoskeleton (also CSK is a cellular " Scaffolding " or " Skeleton " contained within the Cytoplasm. In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells ^[4]

Ligand-gated

Ligand-gated sodium channels are activated by binding of a ligand instead of a change in membrane potential. Sodium channel voltage-gated type I beta, also known as SCN1B, is a human Gene. Sodium channel voltage-gated type II beta, also known as SCN2B, is a human Gene. Sodium channel voltage-gated type III beta, also known as SCN3B, is a human Gene. SCN4B is a Sodium channel associated with Long QT syndrome. See also Sodium channel The Ligand-gated ion channels, also referred to as LGICs, or ionotropic receptors, are a group of intrinsic transmembrane ion channels that are In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally

They are found e. g. in the neuromuscular junction as nicotinic receptors, where the ligands are acetylcholine molecules. A neuromuscular junction ( NMJ) is the Synapse or junction of the Axon terminal of a Motoneuron with the motor end plate, the Structure Nicotinic receptors with a molecular mass of 290 kDa, are made up of five subunits arranged symmetrically around the central pore. The Chemical compound acetylcholine (often abbreviated ACh) is a Neurotransmitter in both the Peripheral nervous system (PNS and Central

Role in action potential

See main article: Action potential

Voltage-gated sodium channels play an important role in action potentials. In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal If enough channels open when there is a change in the cell's membrane potential, a small but significant number of Na⁺ ions will move into the cell down their electrochemical gradient, further depolarizing the cell. Membrane potential (or transmembrane potential) is the Voltage difference (or Electrical potential difference between the interior and exterior of a In Cellular biology, an electrochemical gradient is a spatial variation of both Electrical potential and chemical Concentration across a membrane In biology depolarization is a decrease in the Absolute value of a cell's Membrane potential. Thus, the more Na⁺ channels localized in a region of a cell's membrane, the faster the action potential will propagate, and the more excitable that area of the cell will be. This is an example of a positive feedback loop. Positive feedback, sometimes referred to as "cumulative causation" is a Feedback loop system in which the system responds to perturbation in the same direction The ability of these channels to assume a closed-inactivated state causes the refractory period and is critical for the propagation of action potentials down an axon. In Physiology, a refractory period is a period of time during which an organ or cell is incapable of repeating a particular action or (more precisely the amount of time An axon or nerve fiber is a long slender projectionof a nerve cell or Neuron, that conducts electrical impulses away from the neuron's Cell

Na⁺ channels both open and close more quickly than K⁺ channels, producing an influx of positive charge (Na⁺) toward the beginning of the action potential and an efflux (K⁺) toward the end. In the field of Cell biology, potassium channels are the most widely distributed type of Ion channel and are found in virtually all living organisms In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal

Ligand-gated sodium channels, on the other hand, creates the change in the membrane potential in the first place, in response to the binding of a ligand to it.

Pharmacologic modulation

Blockers

Extracellular

The following naturally produced substances block sodium channels by binding to and occluding the extracellular pore opening of the channel:

• Alkaloid based toxins
  • tetrodotoxin (TTX)
  • saxitoxin

Intracellular

Drugs which block sodium channels by blocking from the intracellular side of the channel:

• Local anesthetics
• Class I antiarrhythmic agents
• Some anticonvulsants

Unknown mechanism

• A-803467: specific blockade of Na_v1. In Cell biology, Molecular biology and related fields the word extracellular (or sometimes extracellular space) means "outside the cell This article is about the chemical compounds alkaloids For the Pharmaceutical company in the Republic of Macedonia see Alkaloid (company. Tetrodotoxin (anhydrotetrodotoxin 4-epitetrodotoxin tetrodonic acid TTX is a potent Neurotoxin with no known antidote which blocks Action potentials in Nerves Saxitoxin ( STX) is a neurotoxin naturally produced by certain species of marine Dinoflagellates ( Alexandrium sp Not to be confused with Intercellular, meaning "between cells" A local anesthetic is a drug that causes reversible Local anesthesia and a loss of Nociception. Antiarrhythmic agents are a group of Pharmaceuticals that are used to suppress fast rhythms of the Heart ( Cardiac arrhythmias) such as Atrial fibrillation The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs" are a diverse group of pharmaceuticals used in the treatment of epileptic 8 channels, developed by Icagen and Abbott Laboratories^[7]

• Caffeine has been shown to inhibit Na+ current in guinea pig ventricular cells. Abbott Laboratories ( is a diversified pharmaceuticals Health care company Caffeine is a bitter white crystalline Xanthine Alkaloid that acts as a Psychoactive Stimulant Drug and a mild Diuretic PubMed

Activators

The following naturally produced substances persistently activate (open) sodium channels:

• Alkaloid based toxins
  • veratridine
  • batrachotoxin
  • aconitine
• Diterpene based toxins
  • grayanotoxin

Gating modifiers

The following toxins modify the gating of sodium channels:

• Peptide based toxins
  • μ-conotoxin
  • δ-atracotoxin^[8]

See also

• Ion channels
• Calcium channels
• Potassium channels
• Resting ion channels
• Epithelial sodium channel

References

External links

• MeSH Sodium+Channels