Voltage-gated sodium channel · Grey Matter

The voltage-gated sodium channel is the membrane protein that opens when the voltage rises past threshold and lets sodium rush in, and it is the part that turns a graded input into an all-or-none action potential.

Voltage-gated sodium channel. The voltage-gated sodium channel is the membrane protein that opens when the voltage rises past threshold and lets sodium rush in, and it is the part that turns a graded input into an all-or-none action potential.

The channel is a pore with a voltage sensor. When the membrane depolarises, the sensor moves and the pore opens within a fraction of a millisecond; sodium enters down its steep gradient, which depolarises the membrane further and opens more channels. That positive feedback is what makes the threshold sharp. About a millisecond later a separate gate plugs the pore (inactivation), and the channel cannot open again until the membrane has returned near rest for a while; this is the cellular basis of the refractory period.

Where the channels sit decides where spikes start. They are packed most densely at the axon initial segment, the first stretch of axon after the cell body (in cortical pyramidal cells mostly the Nav1.6 subtype), and at the nodes of Ranvier of myelinated axons.

Many drugs act here. Local anaesthetics and several antiseizure drugs (carbamazepine, phenytoin, lamotrigine) bind the channel and favour its inactivated state, which damps neurons that fire fast and repeatedly more than neurons at rest.

Mutations matter for excitability. Changes in the genes for these channels are among the best-known genetic causes of epilepsy, and loss of the Nav1.1 subtype, which is important in inhibitory interneurons, weakens inhibition (as in Dravet syndrome).

Channel gating is temperature-sensitive, like most protein kinetics, so warming speeds the opening and the inactivation and shortens the spike.

The sodium channel is the amplifier inside every spike.

Because opening it opens more of it, a small push past threshold becomes a full spike, and its inactivation is what makes the spike end and travel one way.

Questions: How can a drug block sodium channels without stopping every normal spike? Drugs such as carbamazepine bind the voltage-gated sodium channel mainly in its inactivated state, the brief state it enters after opening for each spike. A neuron firing at an ordinary rate spends little time with its channels inactivated, so little drug binds; a neuron firing in a fast burst keeps its channels cycling through that state, the drug accumulates on them and fewer are ready for the next spike. The result, called use-dependent block, trims the long high-frequency runs that seizures are made of while leaving normal firing nearly intact. Why does a neuron either fire a full spike or none at all? Voltage-gated sodium channels open when the membrane depolarises, and the sodium they let in depolarises it further, which opens more of them. Below threshold, potassium leaking out wins and the voltage drifts back; once enough sodium channels open that the inward current outruns the outward one, the feedback runs away and the membrane swings to its peak. The size of the spike is then set by the sodium gradient and the number of channels, never by the size of the input that crossed threshold. This positive feedback was first described quantitatively by Hodgkin and Huxley in the squid giant axon. Where on a neuron does the action potential start, and why there? In most neurons it starts at the axon initial segment, the first few tens of micrometres of axon after the cell body. Sodium channels there are packed several times more densely than on the soma, and the low-threshold Nav1.6 subtype concentrates at its far end, so this is where inputs summed from the dendrites first reach threshold. From there the spike runs forward down the axon and also backward into the soma and dendrites, where it tells the synapses that the cell has fired. Because so much depends on this short stretch, inhibitory chandelier cells that target it, and changes in its length or position, have a strong grip on a neuron's output. Why can a neuron not fire again immediately after a spike, and why does the spike travel only one way? About a millisecond after opening, each sodium channel is plugged by its inactivation gate and stays shut until the membrane has been back near rest for a while, so for that time no input can fire a second spike (the absolute refractory period). Meanwhile potassium channels are still open, holding the voltage low, so for a few milliseconds more only a stronger input succeeds (the relative refractory period). Along the axon, the patch the spike has just left is refractory, so the current can only excite the patch ahead. Together these effects cap the firing rate and make conduction one-way. Why are sodium channels packed into the nodes of Ranvier? In a myelinated axon the spike is regenerated only at the nodes, short gaps about a micrometre long, so each node must produce enough inward current to charge the next internode to threshold. Clustering sodium channels at high density there, held in place by scaffold proteins and flanked by junctions that seal the sheath to the axon, provides that current from a very small area of membrane. It also saves energy, since sodium enters only at the nodes and the pump has less to restore. Varying node length and channel number is one of the ways axons tune their conduction speed.