Sodium channel

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.

Sodium channels are classified into 3 types:

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

Sodium channels are highly selective for transporting sodium ions across cell membranes. The high selectivity with respect to the sodium ion is achieved in many different ways. All involve encapsulating 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.

Voltage-gated Na⁺ channels have three main conformational states: closed, open and inactivated. Forward/back transitions between these states are correspondingly referred to as activation/deactivation (between open and closed, respectively), inactivation/reactivation (between inactivated and open, respectively), and recovery from inactivation/closed-state inactivation (between inactivated and closed, respectively). Closed and inactivated states are ion impermeable.