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Figure 45-7

"Second messenger" system by which a transmitter substance from an initial neuron can activate a second neuron by first releasing a "G-protein" into the second neuron's cytoplasm. Four subsequent possible effects of the G-protein are shown, including 1, opening an ion channel in the membrane of the second neuron; 2, activating an enzyme system in the neuron's membrane; 3, activating an intracellular enzyme system; and/or 4, causing gene transcription in the second neuron.

2. Activation of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) in the neuronal cell. Recall that either cyclic AMP or cyclic GMP can activate highly specific metabolic machinery in the neuron and, therefore, can initiate any one of many chemical results, including long-term changes in cell structure itself, which in turn alters long-term excitability of the neuron.

3. Activation of one or more intracellular enzymes. The G-protein can directly activate one or more intracellular enzymes. In turn the enzymes can cause any one of many specific chemical functions in the cell.

4. Activation of gene transcription. This is one of the most important effects of activation of the second messenger systems because gene transcription can cause formation of new proteins within the neuron, thereby changing its metabolic machinery or its structure. Indeed, it is well known that structural changes of appropriately activated neurons do occur, especially in long-term memory processes.

It is clear that activation of second messenger systems within the neuron, whether they be of the G-protein type or of other types, is extremely important for changing the long-term response characteristics of different neuronal pathways. We will return to this subject in more detail in Chapter 57 when we discuss memory functions of the nervous system.

Excitatory or Inhibitory Receptors in the Postsynaptic Membrane

Some postsynaptic receptors, when activated, cause excitation of the postsynaptic neuron, and others cause inhibition. The importance of having inhibitory as well as excitatory types of receptors is that this gives an additional dimension to nervous function, allowing restraint of nervous action as well as excitation.

The different molecular and membrane mechanisms used by the different receptors to cause excitation or inhibition include the following.

Excitation

1. Opening of sodium channels to allow large numbers of positive electrical charges to flow to the interior of the postsynaptic cell. This raises the intracellular membrane potential in the positive direction up toward the threshold level for excitation. It is by far the most widely used means for causing excitation.

2. Depressed conduction through chloride or potassium channels, or both. This decreases the diffusion of negatively charged chloride ions to the inside of the postsynaptic neuron or decreases the diffusion of positively charged potassium ions to the outside. In either instance, the effect is to make the internal membrane potential more positive than normal, which is excitatory.

3. Various changes in the internal metabolism of the postsynaptic neuron to excite cell activity or, in some instances, to increase the number of excitatory membrane receptors or decrease the number of inhibitory membrane receptors.

Inhibition

1. Opening of chloride ion channels through the postsynaptic neuronal membrane. This allows rapid diffusion of negatively charged chloride ions from outside the postsynaptic neuron to the inside, thereby carrying negative charges inward and increasing the negativity inside, which is inhibitory.

2. Increase in conductance of potassium ions out of the neuron. This allows positive ions to diffuse to the exterior, which causes increased negativity inside the neuron; this is inhibitory.

3. Activation of receptor enzymes that inhibit cellular metabolic functions that increase the number of inhibitory synaptic receptors or decrease the number of excitatory receptors.

Chemical Substances That Function as Synaptic Transmitters

More than 50 chemical substances have been proved or postulated to function as synaptic transmitters. Many of them are listed in Tables 45-1 and 45-2, which give two groups of synaptic transmitters. One group comprises small-molecule, rapidly acting transmitters. The other is made up of a large number of neuropep-tides of much larger molecular size that are usually much more slowly acting.

The small-molecule, rapidly acting transmitters are the ones that cause most acute responses of the nervous system, such as transmission of sensory signals to the brain and of motor signals back to the muscles. The neuropeptides, in contrast, usually cause more prolonged actions, such as long-term changes in numbers of neuronal receptors, long-term opening or closure of certain ion channels, and possibly even long-term changes in numbers of synapses or sizes of synapses.

Table 45-1

Small-Molecule, Rapidly Acting Transmitters

Class I

Acetylcholine Class II: The Amines Norepinephrine Epinephrine Dopamine Serotonin Histamine Class III: Amino Acids Gamma-aminobutyric acid (GABA) Glycine Glutamate Aspartate Class IV Nitric oxide (NO)

Table 45-2

Neuropeptide, Slowly Acting Transmitters or Growth Factors

Hypothalamic-releasing hormones Thyrotropin-releasing hormone Luteinizing hormone-releasing hormone Somatostatin (growth hormone inhibitory factor) Pituitary peptides Adrenocorticotropic hormone (ACTH) b-Endorphin a-Melanocyte-stimulating hormone Prolactin

Luteinizing hormone Thyrotropin Growth hormone Vasopressin Oxytocin Peptides that act on gut and brain Leucine enkephalin Methionine enkephalin Substance P Gastrin

Cholecystokinin

Vasoactive intestinal polypeptide (VIP) Nerve growth factor Brain-derived neurotropic factor Neurotensin Insulin Glucagon From other tissues Angiotensin II Bradykinin Carnosine Sleep peptides Calcitonin

Small-Molecule, Rapidly Acting Transmitters

In most cases, the small-molecule types of transmitters are synthesized in the cytosol of the presynaptic terminal and are absorbed by means of active transport into the many transmitter vesicles in the terminal. Then, each time an action potential reaches the presy-naptic terminal, a few vesicles at a time release their transmitter into the synaptic cleft. This usually occurs within a millisecond or less by the mechanism described earlier. The subsequent action of the small-molecule type of transmitter on the membrane receptors of the postsynaptic neuron usually also occurs within another millisecond or less. Most often the effect is to increase or decrease conductance through ion channels; an example is to increase sodium conductance, which causes excitation, or to increase potassium or chloride conductance, which causes inhibition.

Recycling of the Small-Molecule Types of Vesicles. The vesicles that store and release small-molecule transmitters are continually recycled and used over and over again. After they fuse with the synaptic membrane and open to release their transmitter substance, the vesicle membrane at first simply becomes part of the synaptic membrane. However, within seconds to minutes, the vesicle portion of the membrane invaginates back to the inside of the presynaptic terminal and pinches off to form a new vesicle. And the new vesicular membrane still contains appropriate enzyme proteins or transport proteins required for synthesizing and/or concentrating new transmitter substance inside the vesicle.

Acetylcholine is a typical small-molecule transmitter that obeys the principles of synthesis and release stated earlier. This transmitter substance is synthesized in the presynaptic terminal from acetyl coenzyme A and choline in the presence of the enzyme choline acetyltransferase. Then it is transported into its specific vesicles. When the vesicles later release the acetyl-choline into the synaptic cleft during synaptic neuronal signal transmission, the acetylcholine is rapidly split again to acetate and choline by the enzyme cholinesterase, which is present in the proteoglycan reticulum that fills the space of the synaptic cleft. And then again, inside the presynaptic terminal, the vesicles are recycled; choline is actively transported back into the terminal to be used again for synthesis of new acetylcholine.

Characteristics of Some of the More Important Small-Molecule

Transmitters. The most important of the small-molecule transmitters are the following.

Acetylcholine is secreted by neurons in many areas of the nervous system but specifically by (1) the terminals of the large pyramidal cells from the motor cortex, (2) several different types of neurons in the basal ganglia, (3) the motor neurons that innervate the skeletal muscles, (4) the preganglionic neurons of the autonomic nervous system, (5) the postganglionic neurons of the parasympathetic nervous system, and (6) some of the postganglionic neurons of the sympathetic nervous system. In most instances, acetylcholine has an excitatory effect; however, it is known to have inhibitory effects at some peripheral parasympathetic nerve endings, such as inhibition of the heart by the vagus nerves.

Norepinephrine is secreted by the terminals of many neurons whose cell bodies are located in the brain stem and hypothalamus. Specifically, norepinephrine-secreting neurons located in the locus ceruleus in the pons send nerve fibers to widespread areas of the brain to help control overall activity and mood of the mind, such as increasing the level of wakefulness. In most of these areas, norepinephrine probably activates excitatory receptors, but in a few areas, it activates inhibitory receptors instead. Norepinephrine is also secreted by most postganglionic neurons of the sympathetic nervous system, where it excites some organs but inhibits others.

Dopamine is secreted by neurons that originate in the substantia nigra. The termination of these neurons is mainly in the striatal region of the basal ganglia. The effect of dopamine is usually inhibition.

Glycine is secreted mainly at synapses in the spinal cord. It is believed to always act as an inhibitory transmitter.

GABA (gamma-aminobutyric acid) is secreted by nerve terminals in the spinal cord, cerebellum, basal ganglia, and many areas of the cortex. It is believed always to cause inhibition.

Glutamate is secreted by the presynaptic terminals in many of the sensory pathways entering the central nervous system, as well as in many areas of the cerebral cortex. It probably always causes excitation.

Serotonin is secreted by nuclei that originate in the median raphe of the brain stem and project to many brain and spinal cord areas, especially to the dorsal horns of the spinal cord and to the hypothalamus. Serotonin acts as an inhibitor of pain pathways in the cord, and an inhibitor action in the higher regions of the nervous system is believed to help control the mood of the person, perhaps even to cause sleep.

Nitric oxide is especially secreted by nerve terminals in areas of the brain responsible for long-term behavior and for memory. Therefore, this transmitter system might in the future explain some behavior and memory functions that thus far have defied understanding. Nitric oxide is different from other small-molecule transmitters in its mechanism of formation in the presynaptic terminal and in its actions on the postsynaptic neuron. It is not preformed and stored in vesicles in the presynaptic terminal as are other transmitters. Instead, it is synthesized almost instantly as needed, and it then diffuses out of the presynaptic terminals over a period of seconds rather than being released in vesicular packets. Next, it diffuses into postsynaptic neurons nearby. In the postsynaptic neuron, it usually does not greatly alter the membrane potential but instead changes intracellular metabolic functions that modify neuronal excitability for seconds, minutes, or perhaps even longer.

Neuropeptides

The neuropeptides are an entirely different class of transmitters that are synthesized differently and whose actions are usually slow and in other ways quite different from those of the small-molecule transmitters. The neuropeptides are not synthesized in the cytosol of the presynaptic terminals. Instead, they are synthesized as integral parts of large-protein molecules by ribosomes in the neuronal cell body.

The protein molecules then enter the spaces inside the endoplasmic reticulum of the cell body and subsequently inside the Golgi apparatus, where two changes occur: First, the neuropeptide-forming protein is enzy-matically split into smaller fragments, some of which are either the neuropeptide itself or a precursor of it. Second, the Golgi apparatus packages the neuropep-tide into minute transmitter vesicles that are released into the cytoplasm. Then the transmitter vesicles are transported all the way to the tips of the nerve fibers by axonal streaming of the axon cytoplasm, traveling at the slow rate of only a few centimeters per day. Finally, these vesicles release their transmitter at the neuronal terminals in response to action potentials in the same manner as for small-molecule transmitters. However, the vesicle is autolyzed and is not reused.

Because of this laborious method of forming the neuropeptides, much smaller quantities of them are usually released than of the small-molecule transmitters. This is partly compensated for by the fact that the neuropeptides are generally a thousand or more times as potent as the small-molecule transmitters. Another important characteristic of the neuropeptides is that they often cause much more prolonged actions. Some of these actions include prolonged closure of calcium channels, prolonged changes in the metabolic machinery of cells, prolonged changes in activation or deactivation of specific genes in the cell nucleus, and/or prolonged alterations in numbers of excitatory or inhibitory receptors. Some of these effects last for days, but others perhaps for months or years. Our knowledge of the functions of the neuropeptides is only beginning to develop.

Electrical Events During Neuronal Excitation

The electrical events in neuronal excitation have been studied especially in the large motor neurons of the anterior horns of the spinal cord. Therefore, the events described in the next few sections pertain essentially to these neurons. Except for quantitative differences, they apply to most other neurons of the nervous system as well.

Resting Membrane Potential of the Neuronal Soma. Figure 45-8 shows the soma of a spinal motor neuron, indicating a resting membrane potential of about -65 millivolts. This is somewhat less negative than the -90 millivolts found in large peripheral nerve fibers and in skeletal muscle fibers; the lower voltage is important because it allows both positive and negative control of the degree of excitability of the neuron. That is, decreasing the voltage to a less negative value makes the membrane of the neuron more excitable, whereas increasing this voltage to a more negative value makes the neuron less excitable. This is the basis for the two

Dendrite

(Pumps)

8 mEq/L

Pump

Figure 45-8

Distribution of sodium, potassium, and chloride ions across the neuronal somal membrane; origin of the intrasomal membrane potential.

(Pumps)

8 mEq/L

Pump

modes of function of the neuron—either excitation or inhibition—as explained in detail in the next sections.

Concentration Differences of Ions Across the Neuronal Somal Membrane. Figure 45-8 also shows the concentration differences across the neuronal somal membrane of the three ions that are most important for neuronal function: sodium ions, potassium ions, and chloride ions. At the top, the sodium ion concentration is shown to be high in the extracellular fluid (142mEq/L) but low inside the neuron (14mEq/L). This sodium concentration gradient is caused by a strong somal membrane sodium pump that continually pumps sodium out of the neuron.

The figure also shows that potassium ion concentration is high inside the neuronal soma (120 mEq/L) but low in the extracellular fluid (4.5 mEq/L). It shows that there is a potassium pump (the other half of the Na+-K+ pump) that pumps potassium to the interior.

Figure 45-8 shows the chloride ion to be of high concentration in the extracellular fluid but low concentration inside the neuron. It also shows that the membrane is quite permeable to chloride ions and that there may be a weak chloride pump. Yet most of the reason for the low concentration of chloride ions inside the neuron is the -65 millivolts in the neuron. That is, this negative voltage repels the negatively charged chloride ions, forcing them outward through the pores until the concentration is much less inside the membrane than outside.

Let us recall at this point what we learned in Chapters 4 and 5 about the relation of ionic concentration differences to membrane potentials. It will be recalled that an electrical potential across the cell membrane can oppose movement of ions through a membrane if the potential is of proper polarity and magnitude. A potential that exactly opposes movement of an ion is called the Nernst potential for that ion; the equation for this is the following:

Concentration inside ^ Concentration outside J

where EMF is the Nernst potential in millivolts on the inside of the membrane. The potential will be negative (-) for positive ions and positive (+) for negative ions.

Now, let us calculate the Nernst potential that will exactly oppose the movement of each of the three separate ions: sodium, potassium, and chloride.

For the sodium concentration difference shown in Figure 45-8,142 mEq/L on the exterior and 14 mEq/L on the interior, the membrane potential that will exactly oppose sodium ion movement through the sodium channels calculates to be +61 millivolts. However, the actual membrane potential is -65 millivolts, not +61 millivolts. Therefore, those sodium ions that leak to the interior are immediately pumped back to the exterior by the sodium pump, thus maintaining the -65 millivolt negative potential inside the neuron.

For potassium ions, the concentration gradient is 120 mEq/L inside the neuron and 4.5 mEq/L outside. This calculates to a Nernst potential of -86 millivolts inside the neuron, which is more negative than the

-65 that actually exists. Therefore, because of the high intracellular potassium ion concentration, there is a net tendency for potassium ions to diffuse to the outside of the neuron, but this is opposed by continual pumping of these potassium ions back to the interior.

Finally, the chloride ion gradient, 107 mEq/L outside and 8 mEq/L inside, yields a Nernst potential of -70 millivolts inside the neuron, which is only slightly more negative than the actual measured value of -65 millivolts. Therefore, chloride ions tend to leak very slightly to the interior of the neuron, but those few that do leak are moved back to the exterior, perhaps by an active chloride pump.

Keep these three Nernst potentials in mind and remember the direction in which the different ions tend to diffuse because this information is important in understanding both excitation and inhibition of the neuron by synapse activation or inactivation of ion channels.

Uniform Distribution of Electrical Potential Inside the Soma. The interior of the neuronal soma contains a highly conductive electrolytic solution, the intracellu-lar fluid of the neuron. Furthermore, the diameter of the neuronal soma is large (from 10 to 80 micrometers), causing almost no resistance to conduction of electric current from one part of the somal interior to another part. Therefore, any change in potential in any part of the intrasomal fluid causes an almost exactly equal change in potential at all other points inside the soma (that is, as long as the neuron is not transmitting an action potential). This is an important principle, because it plays a major role in "summation" of signals entering the neuron from multiple sources, as we shall see in subsequent sections of this chapter.

Effect of Synaptic Excitation on the Postsynaptic Membrane— Excitatory Postsynaptic Potential. Figure 45-9 A shows the resting neuron with an unexcited presynaptic terminal resting on its surface. The resting membrane potential everywhere in the soma is -65 millivolts.

Figure 45-95 shows a presynaptic terminal that has secreted an excitatory transmitter into the cleft between the terminal and the neuronal somal membrane. This transmitter acts on the membrane excitatory receptor to increase the membrane's permeability to Na+. Because of the large sodium concentration gradient and large electrical negativity inside the neuron, sodium ions diffuse rapidly to the inside of the membrane.

The rapid influx of positively charged sodium ions to the interior neutralizes part of the negativity of the resting membrane potential. Thus, in Figure 45-9B, the resting membrane potential has increased in the positive direction from -65 to -45 millivolts. This positive increase in voltage above the normal resting neuronal potential—that is, to a less negative value—is called the excitatory postsynaptic potential (or EPSP), because if this potential rises high enough in the positive direction, it will elicit an action potential in the postsynaptic neuron, thus exciting it. (In this case, the

action potential
Figure 45-9

Three states of a neuron. A, Resting neuron, with a normal intraneuronal potential of -65 millivolts. B, Neuron in an excited state, with a less negative intraneuronal potential (-45 millivolts) caused by sodium influx. C, Neuron in an inhibited state, with a more negative intraneuronal membrane potential (-70 millivolts) caused by potassium ion efflux, chloride ion influx, or both.

EPSP is +20 millivolts—that is, 20 millivolts more positive than the resting value.)

However, we must issue a word of warning. Discharge of a single presynaptic terminal can never increase the neuronal potential from -65 millivolts all the way up to -45 millivolts. An increase of this magnitude requires simultaneous discharge of many terminals—about 40 to 80 for the usual anterior motor neuron—at the same time or in rapid succession. This occurs by a process called summation, which is discussed in detail in the next sections.

Generation of Action Potentials in the Initial Segment of the Axon Leaving the Neuron—Threshold for Excitation. When the EPSP rises high enough in the positive direction, there comes a point at which this initiates an action potential in the neuron. However, the action potential does not begin adjacent to the excitatory synapses. Instead, it begins in the initial segment of the axon where the axon leaves the neuronal soma. The main reason for this point of origin of the action potential is that the soma has relatively few voltage-gated sodium channels in its membrane, which makes it difficult for the EPSP to open the required number of sodium channels to elicit an action potential. Conversely, the membrane of the initial segment has seven times as great a concentration of voltage-gated sodium channels as does the soma and, therefore, can generate an action potential with much greater ease than can the soma. The EPSP that will elicit an action potential in the axon initial segment is between +10 and +20 millivolts. This is in contrast to the +30 or +40 millivolts or more required on the soma.

Once the action potential begins, it travels peripherally along the axon and usually also backward over the soma. In some instances, it travels backward into the dendrites, too, but not into all of them, because they, like the neuronal soma, have very few voltage-gated sodium channels and therefore frequently cannot generate action potentials at all. Thus, in Figure 45-95, the threshold for excitation of the neuron is shown to be about -45 millivolts, which represents an EPSP of +20 millivolts—that is, 20 millivolts more positive than the normal resting neuronal potential of -65 millivolts.

Electrical Events During Neuronal Inhibition

Effect of Inhibitory Synapses on the Postsynaptic Membrane— Inhibitory Postsynaptic Potential. The inhibitory synapses open mainly chloride channels, allowing easy passage of chloride ions. Now, to understand how the inhibitory synapses inhibit the postsynaptic neuron, we must recall what we learned about the Nernst potential for chloride ions. We calculated the Nernst potential for chloride ions to be about -70 millivolts. This potential is more negative than the -65 millivolts normally present inside the resting neuronal membrane. Therefore, opening the chloride channels will allow negatively charged chloride ions to move from the extracellular fluid to the interior, which will make the interior membrane potential more negative than normal, approaching the -70 millivolt level.

Opening potassium channels will allow positively charged potassium ions to move to the exterior, and this will also make the interior membrane potential more negative than usual. Thus, both chloride influx and potassium efflux increase the degree of intracel-lular negativity, which is called hyperpolarization. This inhibits the neuron because the membrane potential is even more negative than the normal intracellular potential. Therefore, an increase in negativity beyond the normal resting membrane potential level is called an inhibitory postsynaptic potential (IPSP).

Figure 45-9C shows the effect on the membrane potential caused by activation of inhibitory synapses, allowing chloride influx into the cell and/or potassium efflux out of the cell, with the membrane potential decreasing from its normal value of -65 millivolts to the more negative value of -70 millivolts. This membrane potential is 5 millivolts more negative than normal and is therefore an IPSP of -5 millivolts, which inhibits transmission of the nerve signal through the synapse.

Presynaptic Inhibition

In addition to inhibition caused by inhibitory synapses operating at the neuronal membrane, which is called postsynaptic inhibition, another type of inhibition often occurs at the presynaptic terminals before the signal ever reaches the synapse.This type of inhibition, called presynaptic inhibition, occurs in the following way.

Presynaptic inhibition is caused by release of an inhibitory substance onto the outsides of the presy-naptic nerve fibrils before their own endings terminate on the postsynaptic neuron. In most instances, the inhibitory transmitter substance is GABA (gamma-aminobutyric acid). This has a specific effect of opening anion channels, allowing large numbers of chloride ions to diffuse into the terminal fibril. The negative charges of these ions inhibit synaptic transmission because they cancel much of the excitatory effect of the positively charged sodium ions that also enter the terminal fibrils when an action potential arrives.

Presynaptic inhibition occurs in many of the sensory pathways in the nervous system. In fact, adjacent sensory nerve fibers often mutually inhibit one another, which minimizes sideways spread and mixing of signals in sensory tracts. We discuss the importance of this phenomenon more fully in subsequent chapters.

Time Course of Postsynaptic Potentials

When an excitatory synapse excites the anterior motor neuron, the neuronal membrane becomes highly permeable to sodium ions for 1 to 2 milliseconds. During this very short time, enough sodium ions diffuse rapidly to the interior of the postsynaptic motor neuron to increase its intraneuronal potential by a few millivolts, thus creating the excitatory postsynaptic potential (EPSP) shown by the blue and green curves of Figure 45-10. This potential then slowly declines over the next 15 milliseconds because this is the time required for the excess positive charges to leak out of the excited neuron and to re-establish the normal resting membrane potential.

Precisely the opposite effect occurs for an IPSP; that is, the inhibitory synapse increases the permeability of the membrane to potassium or chloride ions, or both, for 1 to 2 milliseconds, and this decreases the intraneuronal potential to a more negative value than normal, thereby creating the IPSP. This potential also dies away in about 15 milliseconds.

Other types of transmitter substances can excite or inhibit the postsynaptic neuron for much longer periods—for hundreds of milliseconds or even for seconds, minutes, or hours. This is especially true for some of the neuropeptide types of transmitter substances.

"Spatial Summation" in Neurons— Threshold for Firing

Excitation of a single presynaptic terminal on the surface of a neuron almost never excites the neuron. The reason for this is that sufficient transmitter substance is released by a single terminal to cause an EPSP usually no greater than 0.5 to 1 millivolt, instead of the 10 to 20 millivolts normally required to reach threshold for excitation. However, many presynaptic terminals are usually stimulated at the same time. Even though these terminals are spread over wide areas of the neuron, their effects can still summate; that is, they can add to one another until neuronal excitation does occur. The reason for this is the following: It was pointed out earlier that a change in potential at any single point within the soma will cause the potential to change everywhere inside the soma almost exactly equally. This is true because of the very high electrical conductivity inside the large neuronal cell body. Therefore, for each excitatory synapse that discharges simultaneously, the total intrasomal potential becomes more positive by 0.5 to 1.0 millivolt. When

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