Download Chapter notes with neuroscience and more Lecture notes Neuroscience in PDF only on Docsity!
Chapter 3
Introduction to the Action Potential
In the last chapter we showed that cells have a resting potential determined largely, but
not exclusively, by the difference in K+ concentration on the inside of the cell and the
extracellular fluids in which the cells are bathed. All cells have a high permeability to K+
and a much lower permeability for Na+. The small Na+ permeability, however, produces a
constant leakage of positively charged Na+ ions into the cell, which causes the interior of
the cell to be less negative than if it were permeable only to K+ and to no other ion. We
then showed that the resting potential is accurately predicted by the Goldman, Hodgkin
Katz (GHK) equation, an equation similar to, but slightly more complex than, the Nernst
equation. The GHK equation takes the concentration gradient of each ion into account but
weights the contribution of each ion according to the ion’s relative permeability.
Since cells have a resting potential, negative and positive charges are separated by the
cell membranes such that the inside of cells have more negative charges than the outside.
Thus, resting potentials are about -‐70 mV, inside negative relative to outside. The
separation of charges makes each cell a battery. In other words, if a wire, or some other
conductive material connected the inside and outside of the cell, electric current would
flow and could power a device. The entire theme of this chapter is that the cell’s battery, its
resting potential, is the power source that generates action potentials. In order to
understand how action potentials are generated, we first need to more carefully explain ion
channels, and the special types of ion channels, called voltage gated ion channels , that
produce action potentials.
Ion channels are proteins in the cell membrane that confer permeability to ions
The reason that cells have permeabilities for ions is because they have ion channels
inserted into their membranes. Ion channels are proteins with a molecular structure that
creates a central pore (the molecular structure of ion channels will be described in a later
chapter). The important point is that the pore of each ion channel is selectively permeable
to only one ion. It is, therefore, no surprise that neurons, and all other cells, have a large
number of ion channels that are selectively permeable to potassium, which is largely
responsible for their resting potential. These channels are called K+ channels (Fig. 1).
Fig. 1. K
channels in the
membrane are
impermeable to Cl
-‐ and
Na
ions. At the potassium
equilibrium potential, Ek,
equal numbers of K
ions
leave the cell, driven by
the concentration force, as
enter the cell, attracted by
the electrical force. The
movement of K+ ions is
through the pores of K+
channels, which only
allow K+ ions to pass.
If neurons only had K+ channels, their axons could not transmit a signal over long
distances with high fidelity, the features that are the hallmarks of an action potential. If
anything, the signal would die out at a location close to where it was initially generated and
thus the signal would never reach the axon terminal.
Without action potentials, signals on an axon disappear a short distance from where
they are initiated
The reasons for the inability to transmit information over long distances with only K+
channels are illustrated in Fig. 2. The figure shows an axon that has a large number of K+
channels and a normal resting potential of -‐70 mV, inside negative. A short pulse of positive
current (a signal) is then injected into the axon at its end on the far left. The pulse inserts a
fixed number of positive charges into the axon. Let’s trace what happens to these positive
charges (the signal) as they travel down the axon.
Fig. 2. Lower panel shows an axon
being injected with positive
current. The amount of current at
the injection site and the loss of
current along the axon is indicated
by arrows and by thickness of red
triangle. There is no change in
membrane potential at locations
beyond the red triangle because all
the injected current has been lost.
Graph in top panel plots change in
membrane potential as a function
of distance along the axon.
The first point is that the positive charges injected into the axon are attracted to the
negative charges that line the inside of the axon’s membrane. Since charges follow the path
of least resistance, the positive charges move initially to the closest negative charges on the
membrane and then to the negative charges slightly farther down the axon and so on. The
movement of the positive charges then acts to partially neutralize the negative charge (it
makes that portion of the membrane less negative than it was before). There are only a
limited number of positive charges that were injected, and these could only neutralize the
negative charges on a limited length of the axon. There simply are not enough positive
charges to move to sites farther down the axon. In other words, as one moves down the
structure such that a length of amino acids forms a chain-‐like structure that is linked to
another group of amino acids that forms a ball-‐like structure. Thus, when neurons are at
rest, at about -‐70 mV, the activation gate is closed and the inactivation is open. The whole
idea of depolarization is to open the activation gate and close the inactivation gate. However,
an important feature of the two gates is that when the axon is depolarized, the opening of the
activation gate is just slightly faster than the closing of the inactivation gate, as explained
below. The way the channel works is that when the membrane depolarizes, the activation
gate opens quickly allowing for the influx of Na+ ions, and a moment later the channel shuts
off automatically as the ball swings up and plugs the pore. The channel opens, but only for a
fraction of a millisecond, and then closes, automatically by itself.
Fig. 3. Voltage gated sodium channels have two gates, an activation and an inactivation gate. Whether
each gate is open or closed is determined by the membrane potential. 1: At and around the resting
potential, the activation gate is closed and the inactivation gate is open. Because the activation gate is
closed, no Na+ ions can enter the cell. 2 : When the membrane is depolarized, and thus less negative
than at rest, the reduced negativity opens the activation gate, thereby allowing for the influx of Na+
into the cell. 3 : After the activation gate has been open for about 1.0 ms, the slower inactivation gate
swings shut, thereby plugging the pore and preventing the further influx of Na+ ions into the cell. The
closing of the inactivation gate always follows the opening of the activation gate, and acts as a self-‐
limiting gate that allows the pore to be open for only about a 1.0 ms and no longer.
Figure 4 illustrate both the generation and propagation of an action potential as the
gates of the Na+ channels open and close along an axon. We begin at rest (Fig. 4-‐1), when the
activation gate is closed and the inactivation gate is open (i.e., the ball is not plugging the
pore of the channel). Since the activation gate is closed, Na+ ions are prevented from
traveling through the pore, and thus there is no influx of Na+ at rest. A pulse of positive
current is then injected into the axon and the positive current depolarizes the membrane
(Fig. 4-‐2). The depolarization opens the activation gate, and Na+ ions flow into the cell.
Since Na+ is far more concentrated on the outside than the inside of the cell, and the inside of
the cell at rest is about -‐70 mV, Na+ ions are driven into the cell by a concentration force and
are attracted into the cell by its internal negativity (by an electrical force or attraction). In
short, there is a large net force that drives Na+ ions into the cell.
Sodium ions bring positive charges into the part of the cell just under the open Na
channel. Positive Na+ ions entering the cell cause the portion of the membrane just under
the open Na channel to become very positive. Indeed, the membrane potential becomes
increasingly positive with the entry of Na+ ions, until it becomes so positive, that for every
Na+ ion driven in by the concentration force, a Na+ ion will be repelled out of the cell by the
electrical force. In other words, the membrane just under the open Na channel will approach
the sodium equilibrium potential, ENa, which is about +55 mV (inside positive). A moment
later (in less than 1.0 ms) the depolarization causes the inactivation gate to close, thereby
plugging the Na channel and preventing any further influx of Na+ through that channel.
Notice what happened in this brief period of less than 1.0 ms (1/1000 of a second); the
membrane potential spikes from a resting value of -‐70 mV to +55 mV, a net change of 125
mV!
There is now an excess of positive charges under the Na channel. Some of the positive
charges are attracted to the negative charges further down the axon (Fig. 4-‐2). When the
positive charges reach the downstream portion of the axon, they depolarize that part of the
membrane and open the voltage gated Na channels located there. The activation gates on
those channels then open, allow the influx of Na+ ions that drives the membrane potential to
+55 mV, ENa (Fig. 4-‐3). The inactivation gates then quickly close, ending the influx of Na+ (Fig.
4 -‐4). The positive charges at that point then travel down the axon opening the activation
gates in those downstream Na channels, causing the membrane potential to spike to +55 mV,
and the cycle is then repeated all along the axon, as illustrated in Fig. 4.
Fig. 4. Conduction of an action potential by the
sequential opening and closing of voltage gated Na
channels along the length of the axon. The sequences
in panels 1-‐5 are explained in the text.
the opening of K channels is that when the membrane reaches the height of the action
potential (at about +55 mV), the depolarization opens the slower K channels, which then get
rid of the excess positive charges in the axon the efflux of K+ ions. Stated differently, Na+
ions depolarize the cell by bringing positive changes into the cell and the cell is repolarized
by the loss of K+ ions that take the positive charges out of the cells through the delayed
opening of K channels. The reason for that positive charges can be carried in by one ion and
removed by another ion is that the opening (or closing) of channels depends ONLY on the
charge inside the membrane ; the channels do not care which ion carried the charge but
only care about the charge polarity inside the cell. VOLTAGE GATED CHANNELS OPERATE
THOUGH “EQUAL OPPORTUNITY” CHARGES ; they care only about charge and are oblivious
to whether the charge was carried by K+, Na +, or Ca++ ions; the voltage gates on the
channels do not care which ion carries the charge.
Fig. 6. An action potential recorded from the squid giant axon. Lower panel shows the four main
phases of the action potential. See text for further explanation.
The sequence of five events that generate an action potential are described below
and are illustrated by the features of the action potential in Fig. 6 and 7.
- Depolarization of the membrane causes Na channel activation gates to open,
thereby causing an influx of Na+ and quickly driving the membrane potential to +55 mV.
- Repolarization begins less than 1.0 ms after the activation gates open.
Repolarization, bringing the membrane potential back to a very negative value, starts as the
inactivation gates begin to close and shut off the influx of Na+. A small number of positive
charges are lost from the cell through non-‐voltage gated potassium channels, so the
membrane potential becomes less positive, but just by a very small degree.
- The rapid phase of repolarization occurs as the voltage gated potassium channels
open at about the same time as the inactivation gates are closing in the Na channels. Now
the permeability for sodium is virtually zero (because the inactivation gates plug the Na
channels) but potassium permeability is exceptionally high under the membrane that had
just generated an action potential. For a short moment in time, that patch of membrane is
permeable to potassium and only to potassium. There is, therefore, a large efflux of K+,
driven by both its concentration force (K+ is more concentrated inside the cell) and its
electrical force (the inside of the cell is positive at this time, which drives positively charged
K+ ions out of the cell). The efflux of K+ removes so many positive charges that the
membrane at that point quickly becomes so negative that for every K+ driven out by the
concentration force, one is attracted back into the cell by the large negative membrane
potential. Stated differently, because of the massive increase in potassium permeability, the
axonal membrane at that location approaches the potassium equilibrium potential, EK. This
phase of the action potential is called the undershoot, because the membrane potential
“undershoots” the resting potential. i.e., for that brief period the membrane potential is even
more negative than the resting potential.
Fig. 7. The sequence of the actions of the
gates in Na and K channels at each of the 5
phases of an action potential are illustrated in
panels 1-5. Each phase is explained in the
text.
Here is how threshold works. Action potentials are not generated by the opening of a single
sodium channel because the opening of a single sodium channel does not bring in enough
positive Na+ ions to sufficiently change the membrane potential. Rather, the depolarization
needed to generate an action potential is produced by the opening of many sodium channels at
the same time. When a nerve is depolarized, the depolarization evokes two competing events.
First a few sodium channels open thereby increasing the Na
current entering the cell. However,
there is also an increase the amount of K
leaving the cell. This occurs because the influx of the
positive charges carried by Na
makes the inside of the cell less negative. This reduces the
electrical force holding K+ in the cell, and thus the concentration force drives more K+ out of the
cell than it did at a more negative membrane potential. There is a range of small depolarizations
where the Na
entry into the cell, while increased over resting, will still be less than the exit of
K+ ions from the cell. This range of depolarizations is referred to as being “subthreshold”
because no action potentials are evoked by these small depolarizations. Rather after the small
depolarization, the membrane potential returns to rest due to the efflux of K+ ions.
There is, however, a certain depolarization where the entry of Na
is exactly equal to the
exit of K
. This represents the unstable equilibrium point known as “threshold”, where the
membrane teeters between firing and not firing. If, in the next instant, just one more Na
enters
the cell than K
leaves, the membrane will be further depolarized by just a tiny amount. That
tiny, additional depolarization will then open another Na
channel that will bring in more Na+
and initiate the positive feedback shown above. The net result is a rapid, nearly simultaneous
opening of many sodium channels that drives the membrane potential to the sodium equilibrium
potential, E Na
, which is an action potential. Conversely, if, in the next instant one more K
leaves the cell than Na
enters, the membrane potential will begin to return to the resting value.
A definition of threshold for a nerve is, therefore, that value of membrane potential at which the
Na+ current entering the cell is equal to the K
current leaving the cell. For most neurons this is
in the range 10 to 15 mV depolarized from rest.
