Propagation of the Action Potential

So far we’ve been pretending that the action potential occurs only in one place on the cell mem-

brane, but as you know action potentials actually move from place to place. This “propagation” of the

action potential depends not only on voltage-dependent Na+ and K+ channels but on the so-called “pas-

sive” electrical properties of the membrane and on “local potentials”. ("Active" means properties that

change as a function of Vm; "passive" means those that don’t).

Properties of Local Potentials Properties of Action Potentials

Small (subthreshold) large (>100 mV)

Variable in amplitude and duration Constant in amplitude and duration

decrease in size with distance from origin constant in size with distance from origin

Local potentials are a consequence of two resting properties of membranes. First membranes

contain protein pores or channels that allow ions to move from one side of the lipid bilayer to the other,

although it’s much harder for ions to squeeze through these channels than to diffuse around freely in the

cytosol or extracellular fluid. This causes membranes to be “leaky”, which allows some ions to pass

through the membrane and out of the cell.

The second property of membranes is that they are mostly lipid bilayers that are nearly impossible

for ions to cross (except in the relatively rare locations where there are ion channels). The lipid bilayer is

therefore a good insulator, just like the rubber around a copper wire in your appliances. The membrane

can therefore separate charges. Remember that the inside of cells is somewhat negative with respect to the

outside. This charge difference is not uniformly distributed throughout the extracellular and intracellular

fluid; rather it is concentrated near the membrane because opposing charges are attracted to each other,

even through the membrane. The ability of a substance to keep apart charged particles without breaking

down itself is called capacitance. Air is a good capacitor, but if one applies enough charge, what happens?

Air molecules actually ionize and generate a spark.

What effects will the leakiness of the membrane to ions and the ability of the membrane to store

charge have on the ability of nerve cells to conduct electrical signals? Let’s first consider a cylindrical

axon (to make things as simple as possible, not that this is all that simple). (See Fig. 3.10 and Box 3C in

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Purves et al.) If we pass positive charge with an intracellular electrode into the cell at point A, there is a

proportional change in Vm at point A, according to Ohm’s Law. Now what happens at other places in the

neuron? Some of the positive charge that enters the cell at A will be able to move along the axon inside the

cell and part of it will move toward point B. Not all of it will reach point B however, because some will

pass back out at point A or between A and B. Thus fewer charges will reach B than entered at A, and ∆Vm

(a symbol for the change in membrane potential) at B will be <∆Vm at A. How much charge reaches point

B depends on two things--how easily the ions can cross the membrane and back into the extracellular

fluid and how easily they can move through the cytoplasm. Similarly the change in Vm at point C, farther

along the axon, will be less than the change at point B. A graph of this effect is shown in Fig. 3.10C.

(Note, the rate of decline is independent of whether ∆Vm is depolarizing or hyperpolarizing; in either case

the change in membrane potential declines with distance from the initial source of the current until it be-

comes imperceptible a few mm away from the source. The distance over which ΔVm declines to 1/e = 37%

of its original value is called the length constant, λ; a typical value is about 1 mm. See Box C).

So, the effect of the membrane resistance (conductance, leakiness) is to attenuate (i.e., reduce) the

amplitude of ∆Vm at places that are distant from the site on the cell membrane’s surface where the ∆Vm

occurs. Such localized alterations in Vm are quite common--for example, they occur at synapses or at the

ends of neurons called sensory receptors. The reason that such signals are “local” is that they decline in

amplitude over distance until they reach zero--thus some regions of the cell’s membrane have a constant

Vm even when nearby regions are experiencing a change in Vm.

Now I want to consider the effects of the membrane capacitance, or ability to store charge, as well.

If the membrane has some negative charge stored along it, some of the first positive charges entering the

cell neutralize this negative charge, before other positive charges move along inside the axon to neighbor-

ing regions, (where they will also need to neutralize the excess negative charge near the membrane). What

this means is that Vm, the voltage we can measure across the membrane, is initially less when there is ca-

pacitance present than it would be if no capacitance were present. That is, the membrane potential will

eventually become the same absolute value as it would if the membrane had no ability to store charge (ca-

pacitance), but the change in Vm doesn’t happen instantaneously. This can be expressed in mathematical

terms: Q (charge) = V X C (capacitance); differentiating with respect to time:

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 dQ/dt = dV/dt X C; dQ/dt = Ic (capacitive current), so dV/dt = Ic/C. If Ic = 0, dV/dt = 0: if

dV/dt is large, Ic will be large; this is the source of the capacitive current we see during a voltage clamp

experiment. See Fig. 3.10B in Purves et al., Neuroscience. Notice that the shape of the membrane poten-

tial change when current is passed is not "square", but is rounded as it approaches the new Vm or as it re-

turns to the resting potential; that rounding is the effect of the charge-storing capabilities of the mem-

brane.

THUS, the effect of the capacitance of the membrane is to slow down the rate of change of Vm, but

not to alter the final value of Vm compared to a case where there is no capacitance; i.e., the ability of the

charge-storing ability of the membrane is to soak up charges for a while and slow down the rate, but not

the final amount, of the change of Vm.

If we go back to our cylindrical axon and figure in the effects of both leakiness and charge storage

by the membrane, we see that what happens at B, C, D is that the maximum ∆Vm is less than at A (because

of the leakiness of the membrane to ions), and the rate of change of Vm is not instantaneous because of

the time needed to neutralize the accumulated charges near the membrane; this is summarized in Fig.

3.10D. Because subthreshold signals "die out" in this way, they do not conduct information reliably over

long distances. This limitation of neurons is overcome by the action potential (AP).

Once an AP is generated at one site, how is it conducted all along the axon? Consider an axon

that’s more or less cylindrical (Fig. 3.12):

1). Na+ ions enter the axon at A, the site of the AP, making the cell interior more positive at that point.

2.) The current spreads longitudinally along the axon. Since K+ is the most abundant positive ion in-

side the axon, most of the current is caused by K+ ions moving in the cytoplasm. Individual ions move a

short distance, but overall the currents can move fairly long distances (a kind of "domino effect").

3). This ion movement inside the cell makes Vm more positive at distant points along the membrane,

thus reducing the electrical force holding K+ in cells, so K+ ions flow out through the membrane more

rapidly than they do at the resting Vm.

4). Ions (mostly Na+) flow back to point A through the extracellular fluid, completing the circuit.

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 What causes propagation of the AP? If enough current reaches point B, Vm will rise to a value

above threshold, causing an AP to occur there; the same may be true at point C; i.e., the longitudinal

spread of charge (=current) from an AP at point A, causes ∆Vm in adjacent regions of the cell (due to the

cell’s passive electrical properties), which brings Vm up above threshold at those places.

This model is called the “local circuit” model for explaining the conduction of the AP--spread of

current from the point where it enters during the AP causes another AP nearby. This model was actually

established by an ingenious experiment done by Hodgkin when he was an undergraduate at Cambridge

University. He took an axon and laid it on a cold bar just at point B, then stimulated it to form an AP at

point A. Because the membrane was chilled at point B, the voltage-gated Na+ channels didn’t open; in

other words he abolished the ability of the membrane to change its conductance properties in response to

Vm at point B. He then asked what happened at point C. If the action potential had to travel along the

axon’s membrane continuously, then once it stopped at point B, that would be the end of it--no AP could

occur at point C either. But Hodgkin found that even though there was no AP at B, there was one at C.

He concluded that this meant that enough current flowed inside the axon from A to C, through the cooled

region, that it brought Vm at point C up above threshold, and induced a new AP there.

From this explanation, you should be able to figure out what determines how fast the AP travels.

First, if the membrane is very leaky (has a very high permeability to ions, especially K+) compared with

the ease with which K+ moves down the axon, then most charge will flow through the membrane rather

than along the axon, reducing the distance over which Vm rises above threshold.

The membrane capacitance acts like a sponge for charge. Some of the positive charge that enters

at point A gets trapped by negative charges that are sitting next to the membrane and thus they stop flow-

ing down the axon. The more negative charge stored along the membrane, the more of the entering posi-

tive charge gets soaked up and the less that can move down the axon. Both these features --“leakiness”

and high capacitance of membrane--slow the rate of spread of Vm, while impermeability of the membrane

to ions and low capacitance increase the rate of spread. All nerve membranes have some leakiness and

capacitance, making them less than ideal conductors of electrical signals; relay of a signal over a long dis-

tance is impossible without the boost provided by the AP. However it takes time for charge to move from

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one point in the neuron to another point, in order to raise the membrane potential above threshold. The

leakier the membrane or the more charge it has stored, the slower is the spread of charge and thus the

slower is the movement of the AP.

Two things can speed up the rate of transmission of AP. Increasing the radius of the axon in-

creases the ease with which ions can move through the cytoplasm (in electrical terms this decreases the

resistance of the cytoplasm) and thus raises the conduction velocity. Quadrupling the radius roughly

doubles the rate of conduction. So bigger axons conduct faster than small axons. That’s probably why

the squid giant axon is so large--the squid needs very fast conduction for its escape response.

There is limit to this approach; the bigger the axons, the greater will be the volume of the nervous

system. For large organisms with lots of neurons, like us, who need rapid conduction of APs but who

don’t have a lot of space inside our skull for very large axons, this is not viable. So vertebrates have e-

volved a mechanism that requires less increase in size, namely myelination. (See Fig. 3.13 in Purves et al.)

Myelination has two effects. It decreases the leakiness of the membrane to ions, because ions now

have to cross many, many layers of the glial cell membrane (typically 20 or more), as well as the nerve cell

membrane, before they reach the extracellular fluid. As a result it’s very difficult for ions to pass out of

the axons except where there is no myelin--the nodes of Ranvier. Second, myelination greatly reduces the

ability of the membrane to store charge. It separates the intracellular and extracellular fluids so much that

the ions are too far apart and don’t feel an attraction to each other any more, so there’s little accumulated

charge near the membrane to slow down current flow within the axon. Both these changes greatly increase

the likelihood that current will flow along the cytoplasm in the axon rather than crossing the membrane or

being soaked up by charges near it. So both of those features greatly speed up the rate of propagation of

the AP in a myelinated axon.

Myelination also prevents action potentials from happening except at the nodes of Ranvier, be-

cause that’s the only place where voltage dependent sodium channels are located; there are none under the

myelin. This mode of transmission is called saltatory conduction, meaning that the AP jumps from place

to place, but this term is misleading; it implies two things that aren’t true. It suggests that there is no

change in Vm between nodes, but in fact Vm changes everywhere along the axon, under the myelin as well

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as at the nodes. There’s just no change in gNa under the myelin as a result of the ΔVm. Second, many

nodes (10 or so) can fire an AP simultaneously because current can spread that far and bring that many

other nodes up to threshold “downstream” from an active node. That is, the nodes don’t fire one at a

time as I think name salutatory conduction implies. Multiple nodes firing APs simultaneously make con-

duction very fast.

To summarize what we’ve said about propagation of electrical signals:

1). ∆Vm is initiated by a local event such as synaptic transmission or sensory signals.

2). the ∆Vm spreads along the cell by ion flow to adjacent regions.

3.) the membrane is an imperfect conductor of electricity, so that the amplitude and time course of

these changes in Vm are attenuated.

4) If Vm in the “trigger zone” of the neuron is below threshold the signal dies out.

5) If Vm rises above threshold, the rapid increase of gNa and influx of Na+ generates an AP at that

spot on the neuron.

6) This AP is regenerative--i.e. it propagates unattenuated and without fail to end of the axon.

7. The AP is unidirectional because the refractory period prevents Na+ channels from reopening

for a while in response to Vm. That is, the current flows in both direction from the point where it enters

the axon, and raises the Vm both “upstream” and “downstream” from the point of entry. But the volt-

age-gated Na+ channels “upstream” are inactivated and can’t be reactivated to produce another AP, but

the voltage-gated Na+ channels “downstream” can be, so the AP reappears in that direction.

Now sometimes the AP does fail, when it shouldn’t, especially in cases of injury or diseases that

damage the myelin sheath of the neuron, such as multiple sclerosis. The problem there is that the region

between nodes loses myelin and has increased leakiness and capacitance, slowing the spread of ∆Vm from

the node of Ranvier, and there are few voltage-dependent Na+ channels in between nodes so an AP

doesn’t occur further down the axon unless the ∆Vm at the next node is above threshold; often the leaki-

ness and high capacitance of the demyelinated membrane prevents that from happening.