Натриевые каналы: структура, функция и селективность

Transmembrane protein allowing sodium ions in and out
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels.

In excitable cells such as neurons, myocytes, and certain types of glia, sodium channels are responsible for the rising phase of action potentials. These channels go through three different states called resting, active and inactive states. Even though the resting and inactive states would not allow the ions to flow through the channels the difference exists with respect to their structural conformation.

Sodium channels are highly selective for the transport of ions across cell membranes. The high selectivity with respect to the sodium ion is achieved in many different ways. All involve encapsulation of the sodium ion in a cavity of specific size within a larger molecule.

Sodium channels consist of large alpha subunits that associate with accessory proteins, such as beta subunits. An alpha subunit forms the core of the channel and is functional on its own. When the alpha subunit protein is expressed by a cell, it is able to form a pore in the cell membrane that conducts Na+ in a voltage dependent way, even if beta subunits or other known modulating proteins are not expressed. When accessory proteins assemble with α subunits, the resulting complex can display altered voltage dependence and cellular localization. The alpha subunit consists of four repeat domains, labelled I through IV, each containing six membrane spanning segments, labelled S1 through S6. The highly conserved S4 segment acts as the channel's voltage sensor. 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 segment moves toward the extracellular side of the cell membrane, allowing the channel to become permeable to ions. The ions are conducted through the central pore cavity, which consists of two main 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 the pore gate and is formed by the combined S5 and S6 segments of the four domains. The pore domain also features lateral tunnels or fenestrations that run perpendicular to the pore axis. These fenestrations that connect the central cavity to the membrane are proposed to be important for drug accessibility. In mammalian sodium channels, the region linking domains III and IV is also important for channel function. This DIII IV linker is responsible for wedging the pore gate shut after channel opening, inactivating it.

The temporal behavior of Na+ channels can be modeled by a Markovian scheme or by the Hodgkin–Huxley type formalism. 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. 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. The Hodgkin–Huxley model can be shown to be equivalent to a Markovian model.

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. 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. The larger K+ ion cannot fit through this area. Ions of different sizes also cannot interact as well with the negatively charged glutamic acid residues that line the pore.

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

Sodium leak channels do not show any voltage or ligand gating. Instead, they are always open or "leaking" a small background current to regulate the resting membrane potential of a neuron.

Despite following the same basic structure as other sodium channels, NALCN is not sensitive to voltage changes. The voltage sensitive S4 transmembrane domain of NALCN has fewer positively charged amino acids (13 instead of a voltage gated channel's 21) possibly explaining its voltage insensitivity. Substance P and neurotensin both activate Src family kinases through their respective GPCRs (independent of the coupled G proteins) which in turn increase the permeability of NALCN through UNC80 activation. Acetylcholine can also increase NALCN activity through M3 muscarinic acetylcholine receptors. Higher levels of extracellular Ca2+ decrease the permeability of NALCN by activating CaSR which inhibits UNC80.

NALCN complexes with the proteins UNC79, UNC80, and FAM155A. UNC79 appears to be linked to membrane stability of NALCN and linkage with UNC 80. Mutations to NALCN have also been linked to multiple severe developmental disorders and cervical dystonia. Schizophrenia and bipolar disorder are also linked to mutations to NALCN.

Changes in blood and tissue pH accompany physiological and pathophysiological conditions such as exercise, cardiac ischemia, ischemic stroke, and cocaine ingestion. These conditions are known to trigger the symptoms of electrical diseases in patients carrying sodium channel mutations. Protons cause a diverse set of changes to sodium channel gating, which generally lead to decreases in the amplitude of the transient sodium current and increases in the fraction of non inactivating channels that pass persistent currents. These effects are shared with disease causing mutants in neuronal, skeletal muscle, and cardiac tissue and may be compounded in mutants that impart greater proton sensitivity to sodium channels, suggesting a role of protons in triggering acute symptoms of electrical disease.

Single channel data from cardiomyocytes have shown that protons can decrease the conductance of individual sodium channels. The sodium channel selectivity filter is composed of a single residue in each of the four pore loops of the four functional domains. These four residues are known as the DEKA motif. The permeation rate of sodium through the sodium channel is determined by a four carboxylate residues, the EEDD motif, which make up the outer charged ring. One such residue is C373 in the cardiac sodium channel which makes it the most pH sensitive sodium channel among the sodium channels that have been studied to date.

As the cardiac sodium channel is the most pH sensitive sodium channel, most of what is known is based on this channel. Reduction in extracellular pH has been shown to depolarize the voltage dependence of activation and inactivation to more positive potentials. This indicates that during activities that decrease the blood pH, such as exercising, the probability of channels activating and inactivating is higher more positive membrane potentials, which can lead to potential adverse effects. The sodium channels expressed in skeletal muscle fibers have evolved into relatively pH insensitive channels. This has been suggested to be a protective mechanism against potential over or under excitability in skeletal muscles, as blood pH levels are highly susceptible to change during movement. Recently, a mixed syndrome mutation that causes periodic paralysis and myotonia in the skeletal sodium channel has been shown to impart pH sensitivity in this channel, making the gating of this channel similar to that of the cardiac subtype.

The effects of protonation have been characterized in Nav1.1–Nav1.5. Among these channels, Nav1.1–Nav1.3 and Nav1.5 display depolarized voltage dependence of activation, while activation in Nav1.4 remains insensitive to acidosis. The voltage dependence of steady state fast inactivation is unchanged in Nav1.1–Nav1.4, but steady state fast inactivation in Nav1.5 is depolarized. Hence, among the sodium channels that have been studied so far, Nav1.4 is the least and Nav1.5 is the most proton sensitive subtypes.