Sodium ion channel

Sodium channels are integral membrane proteins that exist in a cell's plasma membrane and regulate the flow of sodium (Na+) ions into it. A number of receptors function as Na+-permeable ion channels, including some acetylcholine receptors and ionotropic glutamate receptors. In neuronal signalling, voltage gated sodium channels are especially important because they are responsible for a large part of the depolarization of the cell.

Voltage-gated sodium channels
When closed, sodium channels help to maintain a neuron's resting potential, and when open, they allow sodium ions to flow rapidly down their electrochemical gradient, thus depolarizing the neuron. Voltage-gated Na+ channels are probably genetically related to potassium and calcium channels; in fact, a change of two amino acids will cause the channel to behave as a calcium channel (Kandel, 2000, p. 164).

Structure and gating
The voltage-gated Na+ channel has three known subunits: a large glycoprotein called the &alpha;-subunit, which probably forms the channel's pore, and two smaller polypeptides called &beta;1 and &beta;2 which regulate the function of the &alpha; (Kandel, 2000, p. 164). &gamma;- and &delta;-subunits may also exist to regulate the &alpha;-subunit.

The &alpha;-subunit has four repeats, labeled I through IV, of the same 150 amino acid sequence. Each repeat contains six membrane-spanning regions labeled S1 through S6 (Kandel, 2000, p. 164). The highly conserved S4 region, thought to be the part of the channel that acts as its voltage sensor, has a positive amino acid at every third spot, with hydrophobic residues between these (Kandel, 2000, p. 164). It is thought that when stimulated by a change in transmembrane voltage, this subunit moves from within the pore toward the extracellular side of the cell, allowing the channel to become permeable to ions which would otherwise have been blocked by the subunit's positive charges.

Voltage-gated sodium channels can have three states: resting (closed), activated (open), and inactivated (closed). Channels in the resting 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 (Kandel, 2000, p. 163). 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 (Kandel, 2000, p. 166). During an action potential the channel remains inactivated for a few milliseconds after the neuron is finished depolarizing (Kandel, 2000, p. 156). The inactivation will be removed when the membrane potential of the neuron becomes negative after the falling phase of the action potential. This will allow the channels to be activated again during the next action potential. Genetic diseases that cause Na+ channels to be unable to inactivate cause muscle stiffness because muscles fire repetitive trains of action potentials (Kandel, 2000, p. 169).

Impermeability to other ions
The inner 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 (Kandel, 2000, p. 163). 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 (Kandel, 2000, p. 163-164). 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 (Kandel, 2000, p. 163-164).

Role in action potential
Voltage-gated ion channel sodium channels play a significant role in action potentials. If enough channels open when there is a change in the neuron's membrane potential, a large number of Na+ ions will rush into the cell down their electrochemical gradient, further depolarizing it. Thus the more Na+ channels exist in a neuron's membrane, the faster the action potential will propagate down the axon, and the more excitable that area of the cell will be (Kandel, 2000, p. 160-161). Na+ channels both open and close more quickly than K+ channels, producing an influx of positive charge toward the beginning of the action potential and an efflux toward the end (Kandel, 2000, p. 160-161).

Reference

 * Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed., pp.154-169. McGraw-Hill, New York (2000). ISBN 0838577016