Sodium channel

Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's plasma membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel for such ions, i.e. either a voltage-change ('Voltage-gated', 'voltage-sensitive', or 'voltage-dependent' sodium channel also called 'VGSCs' or 'Nav channel') or a binding of a substance (a ligand) to the channel (ligand-gated sodium channels).Gastrointestinal: Irritable bowel syndrome; Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's plasma membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel for such ions, i.e. either a voltage-change ('Voltage-gated', 'voltage-sensitive', or 'voltage-dependent' sodium channel also called 'VGSCs' or 'Nav channel') or a binding of a substance (a ligand) to the channel (ligand-gated sodium 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 3 different states called resting, active and inactive states. Even though the resting and inactive states wouldn't 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 sodium 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 α subunits that associate with proteins, such as β subunits. An α subunit forms the core of the channel and is functional on its own. When the α subunit protein is expressed by a cell, it is able to form channels that conduct Na+ in a voltage-gated way, even if β 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 α-subunit has 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 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 segments 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. 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. Before an action potential occurs, the axonal membrane is at its normal resting potential, and Na+ channels are in their deactivated state, blocked on the extracellular side by their activation gates. In response to an electric current (in this case, an action potential), the activation gates open, allowing positively charged Na+ ions to flow into the neuron through the channels, and causing the voltage across the neuronal membrane to increase. Because the voltage across the membrane is initially negative, as its voltage increases to and past zero, it is said to depolarize. This increase in voltage constitutes the rising phase of an action potential. At the peak of the action potential, when enough Na+ has entered the neuron and the membrane's potential has become high enough, the Na+ channels inactivate themselves by closing their inactivation gates. The inactivation gate can be thought of as a 'plug' tethered to domains III and IV of the channel's intracellular alpha subunit. Closure of the inactivation gate causes Na+ flow through the channel to stop, which in turn causes the membrane potential to stop rising. With its inactivation gate closed, the channel is said to be inactivated. With the Na+ channel no longer contributing to the membrane potential, the potential decreases back to its resting potential as the neuron repolarizes and subsequently hyperpolarizes itself. This decrease in voltage constitutes the falling phase of the action potential. When the membrane's voltage becomes low enough, the inactivation gate reopens and the activation gate closes in a process called deinactivation. With the activation gate closed and the inactivation gate open, the Na+ channel is once again in its deactivated state, and is ready to participate in another action potential.