Electrically Active Cell Membranes
The functions of the nervous system—sensation, integration, and response—depend on the functions of the neurons underlying these pathways. To understand how neurons are able to communicate, it is necessary to describe the role of an excitable membrane
in generating these signals. The basis of this communication is the action potential, which demonstrates how changes in the membrane can constitute a signal. Looking at the way these signals work in more variable circumstances involves a look at graded potentials, which will be covered in the next section.
Most cells in the body make use of charged particles, ions, to build up a charge across the cell membrane. Previously, this was shown to be a part of how muscle cells work. For skeletal muscles to contract there must be input from a neuron. Both of the cells make use of the cell membrane to regulate ion movement between the extracellular fluid and cytosol.
As you learned in the chapter on cells, the cell membrane is primarily responsible for regulating what can cross the membrane and what stays on only one side. The cell membrane is a phospholipid bilayer, so only substances that can pass directly through the hydrophobic core can diffuse through unaided. Charged particles, which are hydrophilic by definition, cannot pass through the cell membrane without assistance (Figure 8.10). Transmembrane proteins, specifically channel proteins, make this possible. Several channels, as well as specialized energy dependent “ion-pumps,” are necessary to generate a transmembrane potential and to generate an action potential. Of special interest is the carrier protein referred to as the sodium/potassium pump that moves sodium ions (Na+
) out of a cell and potassium ions (K+
) into a cell, thus regulating ion concentration on both sides of the cell membrane.
Figure 8.10. Cell Membrane and Transmembrane ProteinsThe cell membrane is composed of a phospholipid bilayer and has many transmembrane proteins, including different types of channel proteins that serve as ion channels.
The sodium/potassium pump requires energy in the form of adenosine triphosphate (ATP), so it is also referred to as an ATPase. As was explained in the cell chapter, the concentration of Na+
is higher outside the cell than inside, and the concentration of K+
is higher inside the cell is higher than outside. That means that this pump is moving the ions against the concentration gradients for sodium and potassium, which is why it requires energy. In fact, the pump basically maintains those concentration gradients.
Ion channels do not always freely allow ions to diffuse across the membrane. They are opened by certain events, meaning the channels are gated
. Channels can be categorized on the basis of how they are gated. Although these classes of ion channels are found primarily in cells of nervous or muscular tissue, they also can be found in cells of epithelial and connective tissues. A ligand-gated channel
opens because a signaling molecule, a ligand, binds to the extracellular region of the channel and opens the gated channel (Figure 8.11).
Figure 8.11. Ligand-Gated ChannelsWhen the ligand, in this case the neurotransmitter acetylcholine, binds to a specific location on the extracellular surface of the channel protein, the pore opens to allow select ions through. The ions, in this case, are cations of sodium, calcium, and potassium. A mechanically gated channel opens because of a physical distortion of the cell membrane. Many channels associated with the sense of touch (somatosensation) are mechanically gated. For example, as pressure is applied to the skin, these channels open and allow ions to enter the cell. Similar to this type of channel would be the channel that opens on the basis of temperature changes, as in testing the water in the shower (Figure 8.12).
Figure 8.12. Mechanically Gated ChannelsWhen a mechanical change occurs in the surrounding tissue, such as pressure or touch, the channel is physically opened. Thermoreceptors work on a similar principle. When the local tissue temperature changes, the protein reacts by physically opening the channel.
A voltage-gated channel
is a channel that responds to changes in the electrical properties of the membrane in which it is embedded. Normally, the inner portion of the membrane is at a negative voltage. When that voltage becomes less negative, the channel begins to allow ions to cross the membrane (Figure 8.13).
Figure 8.13. Voltage-Gated ChannelsVoltage-gated channels open when the transmembrane voltage changes around them. Amino acids in the structure of the protein are sensitive to charge and cause the pore to open to the selected ion.
A leakage channel
is randomly gated, meaning that it opens and closes at random, hence the reference to leaking. There is no actual event that opens the channel; instead, it has an intrinsic rate of switching between the open and closed states. Leakage channels contribute to the resting transmembrane voltage of the excitable membrane (Figure 8.14).
Figure 8.14. Leakage ChannelsIn certain situations, ions need to move across the membrane randomly. The particular electrical properties of certain cells are modified by the presence of this type of channel.
The Membrane Potential
The electrical state of the cell membrane can have several variations. These are all variations in the membrane potential
. A potential is a distribution of charge across the cell membrane, measured in millivolts (mV). The standard is to compare the inside of the cell relative to the outside, so the membrane potential is a value representing the charge on the intracellular side of the membrane based on the outside being zero, relatively speaking (Figure 8.15).
Figure 8.15. Measuring Charge across a Membrane with a VoltmeterA recording electrode is inserted into the cell and a reference electrode is outside the cell. By comparing the charge measured by these two electrodes, the transmembrane voltage is determined. It is conventional to express that value for the cytosol relative to the outside.
The concentration of ions in extracellular and intracellular fluids is largely balanced, with a net neutral charge. However, a slight difference in charge occurs right at the membrane surface, both internally and externally. It is the difference in this very limited region that has all the power in neurons (and muscle cells) to generate electrical signals, including action potentials.
Before these electrical signals can be described, the resting state of the membrane must be explained. When the cell is at rest, and the ion channels are closed (except for leakage channels which randomly open), ions are distributed across the membrane in a very predictable way. The concentration of Na+
outside the cell is greater than the concentration inside. Also, the concentration of K+
inside the cell is greater than outside. The cytosol contains a high concentration of anions, in the form of phosphate ions and negatively charged proteins. Large anions are a component of the inner cell membrane, including specialized phospholipids and proteins associated with the inner leaflet of the membrane (leaflet is a term used for one side of the lipid bilayer membrane). The negative charge is localized in the large anions.
With the ions distributed across the membrane at these concentrations, the difference in charge is measured at -70 mV, the value described as the resting membrane potential
. The exact value measured for the resting membrane potential varies between cells, but -70 mV is most commonly used as this value. This voltage would actually be much lower except for the contributions of some important proteins in the membrane. Leakage channels allow Na+
to slowly move into the cell or K+
to slowly move out, and the Na+
pump restores them. This may appear to be a waste of energy, but each has a role in maintaining the membrane potential.
The Action Potential
Resting membrane potential describes the steady state of the cell, which is a dynamic process that is balanced by ion leakage and ion pumping. Without any outside influence, it will not change. To get an electrical signal started, the membrane potential has to change.
This starts with a channel opening for Na+
in the membrane. Because the concentration of Na+
is higher outside the cell than inside the cell, ions will rush into the cell that are driven largely by the concentration gradient. Because sodium is a positively charged ion, it will change the relative voltage immediately inside the cell relative to immediately outside. The resting potential is the state of the membrane at a voltage of -70 mV, so the sodium cation entering the cell will cause it to become less negative. This is known as depolarization
, meaning the membrane potential moves toward zero.
The concentration gradient for Na+
is so strong that it will continue to enter the cell even after the membrane potential has become zero, so that the voltage immediately around the pore begins to become positive. The electrical gradient also plays a role, as negative proteins below the membrane attract the sodium ion. The membrane potential will reach +30 mV by the time sodium has entered the cell.
As the membrane potential reaches +30 mV, other voltage-gated channels are opening in the membrane. These channels are specific for the potassium ion. A concentration gradient acts on K+
, as well. As K+
starts to leave the cell, taking a positive charge with it, the membrane potential begins to move back toward its resting voltage. This is called repolarization
, meaning that the membrane voltage moves back toward the -70 mV value of the resting membrane potential.
Repolarization returns the membrane potential to the -70 mV value that indicates the resting potential, but it actually overshoots that value. Potassium ions reach equilibrium when the membrane voltage is below -70 mV, so a period of hyperpolarization occurs while the K+
channels are open. Those K+
channels are slightly delayed in closing, accounting for this short overshoot.
What has been described here is the action potential, which is presented as a graph of voltage over time in Figure 8.16. It is the electrical signal that nervous tissue generates for communication. The change in the membrane voltage from -70 mV at rest to +30 mV at the end of depolarization is a 100-mV change. That can also be written as a 0.1-V change. To put that value in perspective, think about a battery. An AA battery that you might find in a television remote has a voltage of 1.5 V, or a 9-V battery (the rectangular battery with two posts on one end) is, obviously, 9 V. The change seen in the action potential is one or two orders of magnitude less than the charge in these batteries. In fact, the membrane potential can be described as a battery. A charge is stored across the membrane that can be released under the correct conditions. A battery in your remote has stored a charge that is “released” when you push a button.
Figure 8.16. Graph of Action PotentialPlotting voltage measured across the cell membrane against time, the action potential begins with depolarization, followed by repolarization, which goes past the resting potential into hyperpolarization, and finally the membrane returns to rest.
What happens across the membrane of an electrically active cell is a dynamic process that is hard to visualize with static images or through text descriptions. View this animation
to learn more about this process. What is the difference between the driving force for Na+
? And what is similar about the movement of these two ions?
The question is, now, what initiates the action potential? The description above conveniently glosses over that point. But it is vital to understanding what is happening. The membrane potential will stay at the resting voltage until something changes. The description above just says that a Na+
channel opens. Now, to say “a channel opens” does not mean that one individual transmembrane protein changes. Instead, it means that one kind of channel opens. There are a few different types of channels that allow Na+
to cross the membrane. A ligand-gated Na+
channel will open when a neurotransmitter binds to it and a mechanically gated Na+
channel will open when a physical stimulus affects a sensory receptor (like pressure applied to the skin compresses a touch receptor). Whether it is a neurotransmitter binding to its receptor protein or a sensory stimulus activating a sensory receptor cell, some stimulus gets the process started. Sodium starts to enter the cell and the membrane becomes less negative.
A third type of channel that is an important part of depolarization in the action potential is the voltage-gated Na+
channel. The channels that start depolarizing the membrane because of a stimulus help the cell to depolarize from -70 mV to -55 mV. Once the membrane reaches that voltage, the voltage-gated Na+
channels open. This is what is known as the threshold. Any depolarization that does not change the membrane potential to -55 mV or higher will not reach threshold and thus will not result in an action potential. Also, any stimulus that depolarizes the membrane to -55 mV or beyond will cause a large number of channels to open and an action potential will be initiated.
Because of the threshold, the action potential can be likened to a digital event—it either happens or it does not. If the threshold is not reached, then no action potential occurs. If depolarization reaches -55 mV, then the action potential continues and runs all the way to +30 mV, at which K+
causes repolarization, including the hyperpolarizing overshoot. Also, those changes are the same for every action potential, which means that once the threshold is reached, the exact same thing happens. A stronger stimulus, which might depolarize the membrane well past threshold, will not make a “bigger” action potential. Action potentials are “all or none.” Either the membrane reaches the threshold and everything occurs as described above, or the membrane does not reach the threshold and nothing else happens. All action potentials peak at the same voltage (+30 mV), so one action potential is not bigger than another. Stronger stimuli will initiate multiple action potentials more quickly, but the individual signals are not bigger. Thus, for example, you will not feel a greater sensation of pain, or have a stronger muscle contraction, because of the size of the action potential because they are not different sizes.
Propagation of the Action Potential
The action potential is initiated at the beginning of the axon, at what is called the initial segment. There is a high density of voltage-gated Na+
channels so that rapid depolarization can take place here. Going down the length of the axon, the action potential is propagated because more voltage-gated Na+
channels are opened as the depolarization spreads. This spreading occurs because Na+
enters through the channel and moves along the inside of the cell membrane. As the Na+
moves, or flows, a short distance along the cell membrane, its positive charge depolarizes a little more of the cell membrane. As that depolarization spreads, new voltage-gated Na+
channels open and more ions rush into the cell, spreading the depolarization a little farther.
Because voltage-gated Na+
channels are inactivated at the peak of the depolarization, they cannot be opened again for a brief time. Because of this, depolarization spreading back toward previously opened channels has no effect. The action potential must propagate toward the axon terminals; as a result, the polarity of the neuron is maintained, as mentioned above.
Propagation, as described above, applies to unmyelinated axons. When myelination is present, the action potential propagates differently. Sodium ions that enter the cell at the initial segment start to spread along the length of the axon segment, but there are no voltage-gated Na+
channels until the first node of Ranvier. Because there is not constant opening of these channels along the axon segment, the depolarization spreads at an optimal speed. The distance between nodes is the optimal distance to keep the membrane still depolarized above threshold at the next node. As Na+
spreads along the inside of the membrane of the axon segment, the charge starts to dissipate. If the node were any farther down the axon, that depolarization would have fallen off too much for voltage-gated Na+
channels to be activated at the next node of Ranvier. If the nodes were any closer together, the speed of propagation would be slower.
Propagation along an unmyelinated axon is referred to as continuous conduction
; along the length of a myelinated axon, it is saltatory conduction
. Continuous conduction is slow because there are always voltage-gated Na+
channels opening, and more and more Na+
is rushing into the cell. Saltatory conduction is faster because the action potential basically jumps from one node to the next (saltare = “to leap”), and the new influx of Na+
renews the depolarized membrane. Along with the myelination of the axon, the diameter of the axon can influence the speed of conduction. Much as water runs faster in a wide river than in a narrow creek, Na+
-based depolarization spreads faster down a wide axon than down a narrow one. This concept is known as resistance
and is generally true for electrical wires or plumbing, just as it is true for axons, although the specific conditions are different at the scales of electrons or ions versus water in a river.
When an action potential reaches the axon terminals, voltage-gated Ca2+
channels in the membrane of the synaptic end bulb open. The concentration of Ca2+
increases inside the end bulb, and the Ca2+
ion associates with proteins in the outer surface of neurotransmitter vesicles. The Ca2+
facilitates the merging of the vesicle with the presynaptic membrane so that the neurotransmitter is released through exocytosis into the small gap between the cells, known as the synaptic cleft
Once in the synaptic cleft, the neurotransmitter diffuses the short distance to the postsynaptic membrane of the next neuron and interacts with neurotransmitter receptors on the dendrites or cell body. Receptors are specific for the neurotransmitter, and the two fit together like a key and lock. One neurotransmitter binds to its receptor and will not bind to receptors for other neurotransmitters, making the binding a specific chemical event (Figure 8.17).
Figure 8.17. The SynapseThe synapse is a connection between a neuron and its target cell (which is not necessarily a neuron). The presynaptic element is the synaptic end bulb of the axon where Ca2+ enters the bulb to cause vesicle fusion and neurotransmitter release. The neurotransmitter diffuses across the synaptic cleft to bind to its receptor. The neurotransmitter is cleared from the synapse either by enzymatic degradation, neuronal reuptake, or glial reuptake.
Homeostatic Imbalances: Potassium Concentration
Glial cells, especially astrocytes, are responsible for maintaining the chemical environment of the CNS tissue. The concentrations of ions in the extracellular fluid are the basis for how the membrane potential is established and changes in electrochemical signaling. If the balance of ions is upset, drastic outcomes are possible.
Normally the concentration of K+
is higher inside the neuron than outside. After the repolarizing phase of the action potential, K+
leakage channels and the Na+
pump ensure that the ions return to their original locations. Following a stroke or other ischemic event, extracellular K+
levels are elevated. The astrocytes in the area are equipped to clear excess K+
to aid the pump. But when the level is far out of balance, the effects can be irreversible.
Astrocytes can become reactive in cases such as these, which impairs their ability to maintain the local chemical environment. The glial cells enlarge and their processes swell. They lose their K+
buffering ability and the function of the pump is affected, or even reversed. If a Na+
gradient breaks down, this has a more important effect than interrupting the action potential. Glucose transport into cells is coupled with Na+
co-transport. When that is lost, the cell cannot get the energy it needs. In the central nervous system, carbohydrate metabolism is the only means of producing ATP. Elsewhere in the body, cells rely on carbohydrates, lipids, or amino acids to power mitochondrial ATP production. But the CNS does not store lipids in adipocytes (fat cells) as an energy reserve. The lipids in the CNS are in the cell membranes of neurons and glial cells, notably as an integral component of myelin. Proteins in the CNS are crucial to neuronal function, in roles such as channels for electrical signaling or as part of the cytoskeleton. Those macromolecules are not used to power mitochondrial ATP production in neurons.