Every medical student is aware that information is transmitted in the central nervous system mainly in the form of nerve action potentials, called simply "nerve impulses," through a succession of neurons, one after another. However, in addition, each impulse (1) may be blocked in its transmission from one neuron to the next, (2) may be changed from a single impulse into repetitive impulses, or (3) may be integrated with impulses from other neurons to cause highly intricate patterns of impulses in successive neurons. All these functions can be classified as synaptic functions of neurons.
Types of Synapses—Chemical and Electrical
There are two major types of synapses: (1) the chemical synapse and (2) the electrical synapse.
Almost all the synapses used for signal transmission in the central nervous system of the human being are chemical synapses. In these, the first neuron secretes at its nerve ending synapse a chemical substance called a neurotransmitter (or often called simply transmitter substance), and this transmitter in turn acts on receptor proteins in the membrane of the next neuron to excite the neuron, inhibit it, or modify its sensitivity in some other way. More than 40 important transmitter substances have been discovered thus far. Some of the best known are acetylcholine, norepinephrine, epinephrine, histamine, gamma-aminobutyric acid (GABA), glycine, serotonin, and glutamate.
Electrical synapses, in contrast, are characterized by direct open fluid channels that conduct electricity from one cell to the next. Most of these consist of small protein tubular structures called gap junctions that allow free movement of ions from the interior of one cell to the interior of the next. Such junctions were discussed in Chapter 4. Only a few examples of gap junctions have been found in the central nervous system. However, it is by way of gap junctions and other similar junctions that action potentials are transmitted from one smooth muscle fiber to the next in visceral smooth muscle (Chapter 8) and from one cardiac muscle cell to the next in cardiac muscle (Chapter 10).
"One-Way" Conduction at Chemical Synapses. Chemical synapses have one exceedingly important characteristic that makes them highly desirable for transmitting most nervous system signals: they always transmit the signals in one direction: that is, from the neuron that secretes the transmitter substance, called the presynaptic neuron, to the neuron on which the transmitter acts, called the postsynaptic neuron. This is the principle of one-way conduction at chemical synapses, and it is quite different from conduction through electrical synapses, which often transmit signals in either direction.
Think for a moment about the extreme importance of the one-way conduction mechanism. It allows signals to be directed toward specific goals. Indeed, it is this specific transmission of signals to discrete and highly focused areas both within the nervous system and at the terminals of the peripheral nerves that allows the nervous system to perform its myriad functions of sensation, motor control, memory, and many others.
Figure 45-5 shows a typical anterior motor neuron in the anterior horn of the spinal cord. It is composed of three major parts: the soma, which is the main body of the neuron; a single axon, which extends from the soma into a peripheral nerve that leaves the spinal cord; and the dendrites, which are great numbers of branching projections of the soma that extend as much as 1 millimeter into the surrounding areas of the cord.
As many as 10,000 to 200,000 minute synaptic knobs called presynaptic terminals lie on the surfaces of the dendrites and soma of the motor neuron, about 80 to 95 per cent of them on the dendrites and only 5 to 20 per cent on the soma. These presynaptic terminals are the ends of nerve fibrils that originate from many other neurons. Later, it will become evident that many
Typical anterior motor neuron, showing presynaptic terminals on the neuronal soma and dendrites. Note also the single axon.
of these presynaptic terminals are excitatory—that is, they secrete a transmitter substance that excites the postsynaptic neuron. But other presynaptic terminals are inhibitory—they secrete a transmitter substance that inhibits the postsynaptic neuron.
Neurons in other parts of the cord and brain differ from the anterior motor neuron in (1) the size of the cell body; (2) the length, size, and number of dendrites, ranging in length from almost zero to many centimeters; (3) the length and size of the axon; and (4) the number of presynaptic terminals, which may range from only a few to as many as 200,000. These differences make neurons in different parts of the nervous system react differently to incoming synaptic signals and, therefore, perform many different functions.
Presynaptic Terminals. Electron microscopic studies of the presynaptic terminals show that they have varied anatomical forms, but most resemble small round or oval knobs and, therefore, are sometimes called terminal knobs, boutons, end-feet, or synaptic knobs.
Figure 45-6 illustrates the basic structure of a synapse, showing a single presynaptic terminal on the membrane surface of a postsomatic neuron. The presy-naptic terminal is separated from the postsynaptic neuronal soma by a synaptic cleft having a width usually of 200 to 300 angstroms. The terminal has two internal structures important to the excitatory or inhibitory function of the synapse: the transmitter vesicles and the mitochondria. The transmitter vesicles contain the transmitter substance that, when released into the synaptic cleft, either excites or inhibits the postsynaptic neuron—excites if the neuronal membrane contains excitatory receptors, inhibits if the membrane contains inhibitory receptors. The mitochondria provide adenosine triphosphate (ATP),
Physiologic anatomy of the synapse.
which in turn supplies the energy for synethesizing new transmitter substance.
When an action potential spreads over a presynap-tic terminal, depolarization of its membrane causes a small number of vesicles to empty into the cleft. The released transmitter in turn causes an immediate change in permeability characteristics of the postsy-naptic neuronal membrane, and this leads to excitation or inhibition of the postsynaptic neuron, depending on the neuronal receptor characteristics.
Mechanism by Which an Action Potential Causes Transmitter Release from the Presynaptic Terminals—Role of Calcium Ions
The membrane of the presynaptic terminal is called the presynaptic membrane. It contains large numbers of voltage-gated calcium channels. When an action potential depolarizes the presynaptic membrane, these calcium channels open and allow large numbers of calcium ions to flow into the terminal. The quantity of transmitter substance that is then released from the terminal into the synaptic cleft is directly related to the number of calcium ions that enter. The precise mechanism by which the calcium ions cause this release is not known, but it is believed to be the following.
When the calcium ions enter the presynaptic terminal, it is believed that they bind with special protein molecules on the inside surface of the presynaptic membrane, called release sites. This binding in turn causes the release sites to open through the membrane, allowing a few transmitter vesicles to release their transmitter into the cleft after each single action potential. For those vesicles that store the neurotrans-mitter acetylcholine, between 2000 and 10,000 molecules of acetylcholine are present in each vesicle, and there are enough vesicles in the presynaptic terminal to transmit from a few hundred to more than 10,000 action potentials.
Action of the Transmitter Substance on the Postsynaptic Neuron—Function of "Receptor Proteins"
The membrane of the postsynaptic neuron contains large numbers of receptor proteins, also shown in Figure 45-6. The molecules of these receptors have two important components: (1) a binding component that protrudes outward from the membrane into the synaptic cleft—here it binds the neurotransmitter coming from the presynaptic terminal—and (2) an ionophore component that passes all the way through the postsynaptic membrane to the interior of the post-synaptic neuron. The ionophore in turn is one of two types: (1) an ion channel that allows passage of specified types of ions through the membrane or (2) a "second messenger" activator that is not an ion channel but instead is a molecule that protrudes into the cell cytoplasm and activates one or more substances inside the postsynaptic neuron. These substances in turn serve as "second messengers" to increase or decrease specific cellular functions.
Synaptic cleft (200-300 angstroms)
Synaptic cleft (200-300 angstroms)
Soma of neuron
Soma of neuron
Ion Channels. The ion channels in the postsynaptic neuronal membrane are usually of two types: (1) cation channels that most often allow sodium ions to pass when opened, but sometimes allow potassium and/or calcium ions as well, and (2) anion channels that allow mainly chloride ions to pass but also minute quantities of other anions.
The cation channels that conduct sodium ions are lined with negative charges. These charges attract the positively charged sodium ions into the channel when the channel diameter increases to a size larger than that of the hydrated sodium ion. But those same negative charges repel chloride ions and other anions and prevent their passage.
For the anion channels, when the channel diameters become large enough, chloride ions pass into the channels and on through to the opposite side, whereas sodium, potassium, and calcium cations are blocked, mainly because their hydrated ions are too large to pass.
We will learn later that when cation channels open and allow positively charged sodium ions to enter, the positive electrical charges of the sodium ions will in turn excite this neuron. Therefore, a transmitter substance that opens cation channels is called an excitatory transmitter. Conversely, opening anion channels allows negative electrical charges to enter, which inhibits the neuron. Therefore, transmitter substances that open these channels are called inhibitory transmitters.
When a transmitter substance activates an ion channel, the channel usually opens within a fraction of a millisecond; when the transmitter substance is no longer present, the channel closes equally rapidly. The opening and closing of ion channels provide a means for very rapid control of postsynaptic neurons.
"Second Messenger" System in the Postsynaptic Neuron.
Many functions of the nervous system—for instance, the process of memory—require prolonged changes in neurons for seconds to months after the initial transmitter substance is gone. The ion channels are not suitable for causing prolonged postsynaptic neuronal changes because these channels close within milliseconds after the transmitter substance is no longer present. However, in many instances, prolonged postsynaptic neuronal excitation or inhibition is achieved by activating a "second messenger" chemical system inside the postsynaptic neuronal cell itself, and then it is the second messenger that causes the prolonged effect.
There are several types of second messenger systems. One of the most common types uses a group of proteins called G-proteins. Figure 45-7 shows in the upper left corner a membrane receptor protein. A G-protein is attached to the portion of the receptor that protrudes into the interior of the cell. The G-protein in turn consists of three components: an alpha (a) component that is the activator portion of the G-protein, and beta (b) and gamma (g) components that are attached to the alpha component and also to the inside of the cell membrane adjacent to the receptor protein. On activation by a nerve impulse, the alpha portion of the G-protein separates from the beta and gamma portions and then is free to move within the cytoplasm of the cell.
Inside the cytoplasm, the separated alpha component performs one or more of multiple functions, depending on the specific characteristic of each type of neuron. Shown in Figure 45-7 are four changes that can occur. They are as follows: 1. Opening specific ion channels through the postsynaptic cell membrane. Shown in the upper right of the figure is a potassium channel that is opened in response to the G-protein; this channel often stays open for a prolonged time, in contrast to rapid closure of directly activated ion channels that do not use the second messenger system.
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