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Increased membrane Na+ permeability

Increased flow of Na+ into cell

FIGURE 8-19

Positive-feedback relation between membrane depolarization and increased sodium permeability, which leads to the rapid depolarizing phase of the action potential.

brane depolarization; now we are saying that depolarization causes an increase in sodium permeability. Combining these two distinct causal relationships yields the positive-feedback cycle (Figure 8-19) responsible for the depolarizing phase of the action potential: The initial depolarization opens voltage-gated sodium channels so that the membrane permeability to sodium increases. Because of increased sodium permeability, sodium diffuses into the cell; this addition of positive charge to the cell further depolarizes the membrane, which in turn opens still more voltage-gated sodium channels, which produces a still greater increase in sodium permeability, etc. Many cells that have graded potentials cannot form action potentials because they have no voltage-gated sodium channels.

The potassium channels that open during an action potential are also voltage-gated. In fact, their opening is triggered by the same depolarization that opens the sodium channels, but the potassium channel opening is slightly delayed.

What about the inactivation of the voltage-gated sodium channels that opened during the rising phase of the action potential? This is the result of a voltage-induced change in the conformation of the proteins that constitute the channel, which closes the channel after its brief opening.

The generation of action potentials is prevented by local anesthetics such as procaine (Novocaine) and li-docaine (Xylocaine) because these drugs bind to the voltage-gated sodium channels and block them, preventing their opening in response to depolarization. Without action potentials, graded signals generated in the periphery—in response to injury, for example— cannot reach the brain and give rise to the sensation of pain.

Some animals produce toxins that work by interfering with nerve conduction in the same way that local anesthetics do. For example, the puffer fish produces an extremely potent toxin, tetrodotoxin, that binds to voltage-gated sodium channels and prevents the sodium component of the action potential.

Although we have discussed only sodium and potassium channels, in certain areas of neurons and in various nonneural cells calcium channels open in response to membrane depolarization. In some of the nonneural cells, calcium diffusion into the cell through these voltage-gated channels generates action potentials, which are generally prolonged. The inward calcium diffusion also raises calcium concentration within the cell, which, as described in Chapter 7, constitutes an essential part of the signal transduction pathway that couples membrane excitability to events within these cells.

Threshold and the All-or-None Response Not all membrane depolarizations in excitable cells trigger the positive-feedback relationship that leads to an action potential.

The event that initiates the membrane depolarization provides an ionic current that adds positive charge to the inside of the cell, causing the initial depolarization from the resting membrane potential. As the depolarization begins, however, potassium efflux increases above its resting rate because the inside negativity, which tends to keep potassium in the cell, is weaker. Moreover, initial movement of sodium into the cell decreases because of this same lessened negativity; however, also in response to the depolarization, voltage-gated sodium channels open, increasing sodium permeability, which enhances sodium influx. All in all, at this stage potassium exit still exceeds sodium entry. But as the stimulus continues to add current (positive charge) to the inside of the cell, the depolarization increases, and more and more voltage-gated sodium channels open, allowing the influx of sodium ions to increase. Once the point is reached that the sodium influx exceeds potassium efflux, the positivefeedback cycle takes off and an action potential occurs. From this moment on, the membrane events are independent of the initial disturbing event and are driven entirely by the membrane properties.

In other words, action potentials occur only when the net movement of positive charge through ion channels is inward. The membrane potential at which this occurs is called the threshold potential, and stimuli that are just strong enough to depolarize the membrane to this level are threshold stimuli (Figure 8-20).

The threshold of most excitable membranes is about 15 mV less negative than the resting membrane potential. Thus, if the resting potential of a neuron is — 70 mV, the threshold potential may be — 55 mV. At depolarizations less than threshold, outward potassium movement still exceeds sodium entry, and the positive-feedback cycle cannot get started despite the increase in sodium entry. In such cases, the membrane will return to its resting level as soon as the stimulus

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Neural Control Mechanisms CHAPTER EIGHT

Neural Control Mechanisms CHAPTER EIGHT

Action potential

Action potential

Resting potential
Threshold Level Action Potential

Time

FIGURE 8-20

Changes in the membrane potential with increasing strength of depolarizing stimulus. When the membrane potential reaches threshold, action potentials are generated. Increasing the stimulus strength above threshold level does not cause larger action potentials. (The afterhyperpolarization has been omitted from this figure for clarity, and the absolute value of threshold is not indicated because it varies from cell to cell.)

Time

FIGURE 8-20

Changes in the membrane potential with increasing strength of depolarizing stimulus. When the membrane potential reaches threshold, action potentials are generated. Increasing the stimulus strength above threshold level does not cause larger action potentials. (The afterhyperpolarization has been omitted from this figure for clarity, and the absolute value of threshold is not indicated because it varies from cell to cell.)

is removed, and no action potential is generated. These weak depolarizations are subthreshold potentials, and the stimuli that cause them are subthreshold stimuli.

Stimuli of more than threshold magnitude also elicit action potentials, but as can be seen in Figure 8-20, the action potentials resulting from such stimuli have exactly the same amplitude as those caused by threshold stimuli. This is because once threshold is reached, membrane events are no longer dependent upon stimulus strength. Rather, the depolarization generates an action potential because the positive-feedback cycle is operating. Action potentials either occur maximally or they do not occur at all. Another way of saying this is that action potentials are all-or-none. The actual shape and amplitude of the action potential depends on the membrane conditions existing at a given time. For example, if the extracellular sodium concentration changes, the shape of the action potential will change.

The firing of a gun is a mechanical analogy that shows the principle of all-or-none behavior. The magnitude of the explosion and the velocity at which the bullet leaves the gun do not depend on how hard the trigger is squeezed. Either the trigger is pulled hard enough to fire the gun, or it is not; the gun cannot be fired halfway.

Because of its all-or-none nature, a single action potential cannot convey information about the magnitude of the stimulus that initiated it. How then does one distinguish between a loud noise and a whisper, a light touch and a pinch? This information, as we shall see, depends upon the number and pattern of action potentials transmitted per unit of time and not upon their magnitude.

Refractory Periods During the action potential, a second stimulus, no matter how strong, will not produce a second action potential, and the membrane is said to be in its absolute refractory period. This occurs because the voltage-gated sodium channels enter a closed, inactive state at the peak of the action potential. The membrane must repolarize before the sodium channel proteins return to the state in which they can be opened again by depolarization.

Following the absolute refractory period, there is an interval during which a second action potential can be produced, but only if the stimulus strength is considerably greater than usual. This is the relative refractory period, which can last 10 to 15 ms or longer in neurons and coincides roughly with the period of af-terhyperpolarization. During the relative refractory period, there is lingering inactivation of the voltage-gated sodium channels, and an increased number of potassium channels are open. If a depolarization exceeds the increased threshold or outlasts the relative refractory period, additional action potentials will be fired.

The refractory periods limit the number of action potentials that can be produced by an excitable membrane in a given period of time. They also increase the reliability of neural signaling because they help limit extra impulses. Most nerve cells respond at frequencies of up to 100 action potentials per second, and some may produce much higher frequencies for brief periods. Finally, the refractory periods are key in determining the direction of action potential propagation, as will be discussed in the following section.

Action-Potential Propagation As we have seen, the inside of the cell becomes positive with respect to the outside at the site of an action potential. This area of the membrane is also positive with respect to other regions where the membrane is still at its resting potential. The difference in potentials between the active and resting regions causes ions to flow, and this local current depolarizes the membrane adjacent to the action-potential site to its threshold potential. The sodium positive-feedback cycle takes over, and a new action potential occurs there.

PART TWO Biological Control Systems

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems

Direction of action potential propagation

Site of original action potential

Repolarized; membrane restored to resting conditions

Site of present action potential

Extracellular fluid

Repolarized; membrane in relative refractory period

Depolarized

FIGURE 8-21

Propagation of an action potential along a plasma membrane.

Intracellular fluid

Polarized but soon to be depolarized by local current from adjacent site

The new action potential then produces local currents of its own, which depolarize the region adjacent to it, producing yet another action potential at the next site, and so on to cause action-potential propagation along the length of the membrane. Thus, there is a sequential opening and closing of sodium and potassium channels along the membrane. It is like lighting a trail of gunpowder; the action potential doesn't move but "sets off" a new action potential in the region of the axon just ahead of it. Because each action potential depends on the sodium-feedback cycle of the membrane where the action potential is occurring, the action potential arriving at the end of the membrane is virtually identical in form to the initial one. Thus, action potentials are not conducted decrementally as are graded potentials.

Because the membrane areas that have just undergone an action potential are refractory and cannot immediately undergo another, the only direction of action potential propagation is away from a region of membrane that has recently been active (Figure 8-21).

If the membrane through which the action potential must travel is not refractory, excitable membranes are able to conduct action potentials in either direction, the direction of propagation being determined by the stimulus location. For example, the action potentials in skeletal-muscle cells are initiated near the middle of these cylindrical cells and propagate toward the two ends. In most nerve cells, however, action potentials are initiated physiologically at one end of the cell (for reasons to be described in the next section) and propagate toward the other end. The propagation ceases when the action potential reaches the end of an axon.

The velocity with which an action potential propagates along a membrane depends upon fiber diameter and whether or not the fiber is myelinated. The larger the fiber diameter, the faster the action potential propagates. This is because a large fiber offers less resistance to local current; more ions will flow in a given time, bringing adjacent regions of the membrane to threshold faster.

Myelin is an insulator that makes it more difficult for charge to flow between intracellular and extracellular fluid compartments. Because there is less "leakage" of charge across the myelin, the graded potential can spread farther along the axon. Moreover, the concentration of voltage-gated sodium channels in the myelinated region of axons is low. Therefore, action potentials occur only at the nodes of Ranvier where the myelin coating is interrupted and the concentration of voltage-gated sodium channels is high. Thus, action potentials literally jump from one node to the next as they propagate along a myelinated fiber, and for this reason such propagation is called saltatory conduction (Latin, saltare, to leap).

Propagation via saltatory conduction is faster than propagation in nonmyelinated fibers of the same axon diameter because less charge leaks out through the myelin-covered sections of the membrane (Figure 8-22). More charge arrives at the node adjacent to the active node, and an action potential is generated there sooner than if the myelin were not present. Moreover, because ions cross the membrane only at the nodes of Ranvier, the membrane pumps need restore fewer ions. Myelinated axons are therefore metabolically more

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Neural Control Mechanisms CHAPTER EIGHT

Neural Control Mechanisms CHAPTER EIGHT

Site of present action potential

Site of present action potential fluid fluid

(b) Site of present action potential

(b) Site of present action potential

Extracellular fluid ,

©

©

Intracellular fluid

-

Current during an action potential in (a) a myelinated and (b) an unmyelinated axon.

cost-effective than unmyelinated ones. Thus, myelin adds efficiency in speed and metabolic cost, and it saves room in the nervous system because the axons can be thinner.

Conduction velocities range from about 0.5 m/s (1 mi/h) for small-diameter, unmyelinated fibers to about 100 m/s (225 mi/h) for large-diameter, myelinated fibers. At 0.5 m/s, an action potential would travel the distance from the head to the toe of an average-sized person in about 4 s; at a velocity of 100 m/s, it takes about 0.02 s.

Initiation of Action Potentials In our description of action potentials thus far, we have spoken of "stimuli" as the initiators of action potentials. How are action potentials actually initiated in various types of neurons?

In afferent neurons, the initial depolarization to threshold is achieved by a graded potential—here called a receptor potential, which is generated in the sensory receptors at the peripheral ends of the neurons. These are the ends farthest from the central nervous system, and where the nervous system functionally encounters the outside world. In all other neurons, the depolarization to threshold is due either to a graded potential generated by synaptic input to the neuron or to a spontaneous change in the neuron's membrane potential, known as a pacemaker potential. How synaptic potentials are produced is the subject of the next section. The production of receptor potentials is discussed in Chapter 9.

Spontaneous generation of pacemaker potentials occurs in the absence of any identifiable external stimulus and is an inherent property of certain neurons (and other excitable cells, including certain smooth-muscle and cardiac-muscle cells). In these cells, the activity of different types of ion channels in the plasma membrane causes a graded depolarization of the membrane—the pacemaker potential. If threshold is reached, an action potential occurs; the membrane then repolarizes and again begins to depolarize (Figure 8-23). There is no stable, resting membrane potential in such cells because of the continuous change in membrane permeability. The rate at which the membrane depolarizes to threshold determines the

Pacemaker Action Potential

FIGURE 8-23

Action potentials resulting from pacemaker potentials.

FIGURE 8-23

Action potentials resulting from pacemaker potentials.

PART TWO Biological Control Systems

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems

TABLE 8-5 Differences between Graded Potentials and Action Potentials

Graded Potential

Action Potential

Amplitude varies with conditions of the initiating event

All-or-none once membrane is depolarized to threshold, amplitude is independent of initiating event

Can be summed

Cannot be summed

Has no threshold

Has a threshold that is usually about 15 mV depolarized relative to the resting potential

Has no refractory period

Has a refractory period

Is conducted decrementally; that is, amplitude decreases with distance

Is conducted without decrement; the depolarization is amplified to a constant value at each point along the membrane

Duration varies with initiating conditions

Duration constant for a given cell type under constant conditions

Can be a depolarization or a hyperpolarization

Is a depolarization (with overshoot in neurons)

Initiated by environmental stimulus (receptor), by neurotransmitter (synapse), or spontaneously

Initiated by a graded potential

Mechanism depends on ligand-sensitive channels or other chemical or physical changes

Mechanism depends on voltage-gated channels

action-potential frequency. Pacemaker potentials are II. implicated in many rhythmical behaviors, such as breathing, the heartbeat, and movements within the walls of the stomach and intestines. III

The differences between graded potentials and action potentials are listed in Table 8-5.

SECTION B SUMMARY

The Resting Membrane Potential

I. Membrane potentials are generated mainly by diffusion of ions and are determined by (a) the ionic concentration differences across the membrane, and (b) the membrane's relative permeabilities to different ions.

a. Plasma-membrane Na,K-ATPase pumps maintain intracellular sodium concentration low and potassium high.

b. In almost all resting cells, the plasma membrane is much more permeable to potassium than to sodium, so the membrane potential is close to the potassium equilibrium potential—that is, the inside is negative relative to the outside.

c. The Na,K-ATPase pumps also contribute directly a small component of the potential because they are electrogenic.

Graded Potentials and Action Potentials

I. Neurons signal information by graded potentials and action potentials (APs).

Graded potentials are local potentials whose magnitude can vary and that die out within 1 or 2 mm of their site of origin.

An AP is a rapid change in the membrane potential during which the membrane rapidly depolarizes and repolarizes. In neurons, the potential reverses and the membrane becomes positive inside. APs provide long-distance transmission of information through the nervous system.

a. APs occur in excitable membranes because these membranes contain voltage-gated sodium channels, which open as the membrane depolarizes, causing a positive feedback toward the sodium equilibrium potential.

b. The AP is ended as the sodium channels close and additional potassium channels open, which restores the resting conditions.

c. Depolarization of excitable membranes triggers APs only when the membrane potential exceeds a threshold potential.

d. Regardless of the size of the stimulus, if the membrane reaches threshold, the APs generated are all the same size.

e. A membrane is refractory for a brief time even though stimuli that were previously effective are applied.

f. APs are propagated without any change in size from one site to another along a membrane.

g. In myelinated nerve fibers, APs manifest saltatory conduction.

h. APs can be initiated by receptors at the ends of afferent neurons, at synapses, or in some cells, by pacemaker potentials.

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Neural Control Mechanisms CHAPTER EIGHT

Neural Control Mechanisms CHAPTER EIGHT

SECTION B KEY TERMS

electric potential potential difference potential current resistance Ohm's law resting membrane potential equilibrium potential electrogenic pump depolarized overshoot repolarizing hyperpolarized graded potential decremental action potential excitable membrane excitability afterhyperpolarization threshold potential threshold stimulus subthreshold potential subthreshold stimulus all-or-none absolute refractory period relative refractory period action-potential propagation saltatory conduction receptor potential pacemaker potential

SECTION B REVIEW QUESTIONS

1. Describe how negative and positive charges interact.

2. Contrast the abilities of intracellular and extracellular fluids and membrane lipids to conduct electric current.

3. Draw a simple cell; indicate where the concentrations of Na+, K+, and Cl" are high and low and the electric -potential difference across the membrane when the cell is at rest.

4. Explain the conditions that give rise to the resting membrane potential. What effect does membrane permeability have on this potential? What is the role of Na,K-ATPase membrane pumps in the membrane potential? Is this role direct or indirect?

5. Which two factors involving ion diffusion determine the magnitude of the resting membrane potential?

6. Explain why the resting membrane potential is not equal to the potassium equilibrium potential.

7. Draw a graded potential and an action potential on a graph of membrane potential versus time. Indicate zero membrane potential, resting membrane potential, and threshold potential; indicate when the membrane is depolarized, repolarizing, and hyperpolarized.

8. List the differences between graded potentials and action potentials.

9. Describe the ionic basis of an action potential; include the role of voltage-gated channels and the positive-feedback cycle.

10. Explain threshold and the relative and absolute refractory periods in terms of the ionic basis of the action potential.

11. Describe the propagation of an action potential. Contrast this event in myelinated and unmyelinated axons.

12. List three ways in which action potentials can be initiated in neurons.

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