Voltage Gated Sodium Channels

Transmembrane Domains

In this section, we examine the voltage-gated sodium channel as a specific example of a protein embedded in the plasma membrane. This type of protein is found in the nerve and muscle cells and is used in the rapid electrical signalling found in these cells. The principle subunit of the voltage-gated sodium channel is a polypeptide chain of more than 1800 amino acids.

When the amino acid sequence of any protein embedded in a membrane is examined, typically one or more segments of the polypeptide chain are found to be comprised largely of amino acids with nonpolar side chains. Each of these segments coils is what is called a transmembrane domain, with a length approximately the width of the membrane. Moreover, within a transmembrane domain the side chains necessarily face outward where they readily interact with the lipids of the membrane. By contrast, the peptide bonds, which are quite polar, face inward, separated from the lipid environment of the membrane.

In the case of the voltage-gated sodium channel, there are 24 such transmembrane domains in the polypeptide chain, as shown to the right.

For clarity in the figure to the right, the alpha-helices are shown spread out and in a row. Also, they are shown divided into four groups. Each of these is an homologous domain with a similar sequence of amino acids.

In an actual membrane, of course, the alpha-helices are not in a line, but clustered. This is shown in top view in the figure to the left. At the center of the four domains is the channel through which the sodium ions move.

Opening of Channel by Voltage Sensor

The voltage-gated sodium channel has several functional parts. One portion of the channel determines its ion selectivity. This particular channel is quite selective for sodium ions. Even the chemically similar potassium ions cannot pass through the channel.

Another portion of the channel serves as a gate that can open and close. For many ion channels, the gate opens in response to regulatory molecules that specifically bind to either the inside or outside of the channel. But in the case of the voltage-gated sodium channel, the gate is controlled by a voltage sensor, which responds to the level of the membrane potential.

The membrane potential is designated at the left of the figure by the net excess of positive and negative changes. As shown, cells in general have a small net excess of negative ions clustered under the plasma membrane. In a resting neuron or muscle cell the inside is approximately 70 to 90 millivolts (mV) negative with respect to outside.

In this diagram and those that follow, a single transmembrane domain is shown as the voltage sensor that operates the gate. This is for diagrammatic simplicity. Actually, several voltage sensors must respond before the gate opens.

Finally, an inactivation gate is shown. This limits the period of time the channel remains open, despite steady stimulation. But many other types of ion channels do not have an inactivation gate.

The figure to the left shows the movement of the voltage sensor during changes in the membrane potential. The voltage sensor is represented as a transmembrane domain with fixed positive charges. Each of the homologous domains, in fact, has one transmembrane domain in which a positively charged amino acid is found at every third position, giving a total of four to eight positive charges per transmembrane domain. These transmembrane domains are likely to be the actual voltage sensors.

At a typical resting membrane potential (for example, -70 mV) the channel is closed. Then should any factor depolarize the membrane potential sufficiently (for example, to -50 mV), the voltage sensor moves outward and the gate opens. (Figures of channel based on figures by B. Hille and B. Zagotta.)