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10
Overview of Synaptic Transmission
Eric R. Kandel
Steven A. Siegelbaum
WHAT GIVES NERVE CELLS their special ability to communicate with one another so rapidly, over such great distances, and with such tremendous precision? We have
already seen how signals are propagated within a neuron, from its dendrites and cell body to its axonal terminal. Beginning with this chapter we consider the cellular
mechanisms for signaling between neurons. The point at which one neuron communicates with another is called a synapse, and synaptic transmission is fundamental to
many of the processes we consider later in the book, such as perception, voluntary movement, and learning.
The average neuron forms about 1000 synaptic connections and receives even more, perhaps as many as 10,000 connections. The Purkinje cell of the cerebellum
receives up to 100,000 inputs. Although many of these connections are highly specialized, all neurons make use of one of two basic forms of synaptic transmission:
electrical or chemical. Moreover, the strength of both forms of synaptic transmission can be enhanced or diminished by cellular activity. This plasticity in nerve cells is
crucial to memory and other higher brain functions.
In the brain, electrical synaptic transmission is rapid and rather stereotyped. Electrical synapses are used primarily to send simple depolarizing signals; they do not lend
themselves to producing inhibitory actions or making long-lasting changes in the electrical properties of postsynaptic cells. In contrast, chemical synapses are capable of
more variable signaling and thus can produce more complex behaviors. They can mediate either excitatory or inhibitory actions in postsynaptic cells and produce
electrical changes in the postsynaptic cell that last from milliseconds to many minutes. Chemical synapses also serve to amplify neuronal signals, so that even a small
presynaptic nerve terminal can alter the response of a large postsynaptic cell. Because chemical synaptic transmission is so central to understanding brain and behavior,
it is examined in detail in Chapters 11, 12, and 13.
Synapses Are Either Electrical or Chemical
The term synapse was introduced at the turn of the century by Charles Sherrington to describe the specialized zone of contact at which one neuron communicates with
another; this site had first been described histologically (at the level of light microscopy) by Ramón y Cajal. Initially, all synapses were thought to operate by means of
electrical transmission. In the 1920s, however, Otto Loewi showed that acetylcholine (ACh), a chemical compound, conveys signals from the vagus nerve to the
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heart. Loewi's discovery in the heart provoked considerable debate in the 1930s over how chemical signals could generate electrical activities at other synapses,
including nerve-muscle synapses and synapses in the brain.
Table 10-1 Distinguishing Properties of Electrical and Chemical Synapses
Type of
synapse
Electrical
Chemical
Cytoplasmic
Distance between pre- continuity between
and postsynaptic cell pre- and postsynaptic
cells
membranes
3.5 nm
20-40 nm
Yes
No
Ultrastructural
components
Gap-junction channels
Presynaptic vesicles and active
zones; postsynaptic receptors
Agent of transmission
Ion current
Chemical transmitter
Synaptic delay
Virtually absent
Significant: at least
0.3 ms, usually 1-5
Direction of
transmission
Usually bidirectional
Unidirectional
ms or longer
Two schools of thought emerged, one physiological and the other pharmacological. Each championed a single mechanism for all synaptic transmission. The
physiologists, led by John Eccles (Sherrington's student), argued that all synaptic transmission is electrical, that the action potential in the presynaptic neuron generates
a current that flows passively into the postsynaptic cell. The pharmacologists, led by Henry Dale, argued that transmission is chemical, that the action potential in the
presynaptic neuron leads to the release of a chemical substance that in turn initiates current flow in the postsynaptic cell.
Figure 10-1 Current flows differently at electrical and chemical synapses.
A. At an electrical synapse some of the current injected into a presynaptic cell escapes through resting ion channels in the cell membrane. However, some current also
flows into the postsynaptic cell through specialized ion channels, called gap-junction channels, that connect the cytoplasm of the pre- and postsynaptic cells.
B. At chemical synapses all of the injected current escapes through ion channels in the presynaptic cell. However, the resulting depolarization of the cell activates the
release of neurotransmitter molecules packaged in synaptic vesicles (open circles), which then bind to receptors on the postsynaptic cell. This binding opens ion
channels, thus initiating a change in membrane potential in the postsynaptic cell.
When physiological techniques improved in the 1950s and 1960s it became clear that both forms of transmission exist. Although most synapses use a chemical
transmitter, some operate purely by electrical means. Once the fine structure of synapses was made visible with the electron microscope, chemical and electrical
synapses were found to have different morphologies. At chemical synapses neurons are separated completely by a small space, the synaptic cleft. There is no continuity
between the cytoplasm of one cell and the next. In contrast, at electrical synapses the pre- and postsynaptic cells communicate through special channels, the gapjunction channels, that serve as conduits between the cytoplasm of the two cells.
The main functional properties of the two types of synapses are summarized in Table 10-1. The most important differences can be observed by injecting current
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into the presynaptic cell to elicit a signal (Figure 10-1). At both types of synapses the current flows outward across the presynaptic cell membrane. This current deposits
a positive charge on the inside of the presynaptic cell membrane, reducing its negative charge and thereby depolarizing the cell (see Chapter 8).
Figure 10-2 Electrical synaptic transmission was first demonstrated to occur at the giant motor synapse in the crayfish. (Adapted from Furshpan and
Potter 1957 and 1959.)
A. The presynaptic neuron is the lateral giant fiber running down the nerve cord. The postsynaptic neuron is the motor fiber, which projects from the cell body in the
ganglion to the periphery. The electrodes for passing current and for recording voltage are placed within both the pre- and postsynaptic cells.
B. Transmission at an electrical synapse is virtually instantaneous—the postsynaptic response follows presynaptic stimulation in a fraction of a millisecond. The dashed
line shows how the responses of the two cells correspond in time. In contrast, at chemical synapses there ia a delay between the pre- and postsynaptic potentials (see
Figure 10-7).
At electrical synapses the gap-junction channels that connect the pre- and postsynaptic cells provide a low-resistance (high conductance) pathway for electrical current
to flow between the two cells. Thus, some of the current injected in the presynaptic cell flows through these channels into the postsynaptic cell. This current deposits a
positive charge on the inside of the membrane of the postsynaptic cell and depolarizes it. The current then flows out through resting ion channels in the postsynaptic cell
(Figure 10-1A). If the depolarization exceeds threshold, voltage-gated ion channels in the postsynaptic cell will open and generate an action potential.
At chemical synapses there is no direct low-resistance pathway between the pre- and postsynaptic cells. Thus, current injected into a presynaptic cell flows out of the
cell's resting channels into the synaptic cleft, the path of least resistance. Little or no current crosses the external membrane of the postsynaptic cell, which has a high
resistance (Figure 10-1B). Instead, the action potential in the presynaptic neuron initiates the release of a chemical transmitter, which diffuses across the synaptic cleft
to interact with receptors on the membrane of the postsynaptic cell. Receptor activation causes the cell either to depolarize or to hyperpolarize.
Electrical Synapses Provide Instantaneous Signal Transmission
At electrical synapses the current that depolarizes the postsynaptic cell is generated directly by the voltage-gated ion channels of the presynaptic cell. Thus these
channels not only have to depolarize the presynaptic cell above the threshold for an action potential, they must also generate sufficient ionic current to produce a
change in potential in the postsynaptic cell. To generate such a large current, the presynaptic terminal has to be large enough for its membrane to contain a large
number of ion channels. At the same time, the postsynaptic cell has to be relatively small. This is because a small cell has a higher input resistance (Rin) than a large
cell and,
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according to Ohm's law (∆V = ∆I × Rin), will undergo a greater voltage change (∆V) in response to a given presynaptic current (∆I).
Figure 10-3 Electrical transmission is graded and occurs even when the currents in the presynaptic cell are below the threshold for an action
potential. This can be demonstrated by depolarizing the presynaptic cell with a small outward current pulse. Current is passed by one electrode while the membrane
potential is recorded with a second electrode. A subthreshold depolarizing stimulus causes a passive depolarization in the presynaptic and postsynaptic cells. (Outward,
depolarizing current is indicated by upward deflection.)
Electrical synaptic transmission was first described in the giant motor synapse of the crayfish, where the presynaptic fiber is much larger than the postsynaptic fiber
(Figure 10-2A). An action potential generated in the presynaptic fiber produces a depolarizing post- synaptic potential that is often large enough to discharge an action
potential. The latency—the time between the presynaptic spike and the postsynaptic potential—is remarkably short (Figure 10-2B).
Such a short latency is incompatible with chemical transmission, which requires several biochemical steps: release of a transmitter from the presynaptic neuron,
diffusion of the transmitter to the postsynaptic cell, binding of the transmitter to a specific receptor, and subsequent gating of ion channels (all described later in this
chapter). Only current flowing directly from one cell to another can produce the near-instantaneous transmission observed at the giant motor synapse.
Further evidence for electrical transmission is that the change in potential of the postsynaptic cell is directly related to the size and shape of the change in potential of
the presynaptic cell. At an electrical synapse any amount of current in the presynaptic cell triggers a response in the postsynaptic cell. Even when a subthreshold
depolarizing current is injected into the pre- synaptic neuron, current flows into the postsynaptic cell and depolarizes it (Figure 10-3). In contrast, at a chemical synapse
the presynaptic current must reach the threshold for an action potential before the cell can release transmitter.
Most electrical synapses will transmit both depolarizing and hyperpolarizing currents. A presynaptic action potential that has a large hyperpolarizing afterpotential will
produce a biphasic (depolarizing-hyperpolarizing) change in potential in the postsynaptic cell. Transmission at electrical synapses is similar to the passive electrotonic
propagation of subthreshold electrical signals along axons (see Chapter 8) and therefore is often referred to as electrotonic transmission. Electrotonic transmission has
been observed even at junctions where, unlike the giant motor synapse of the crayfish, the pre- and postsynaptic elements are similar in size. Because signaling
between neurons at electrical synapses depends on the passive electrical properties at the synapse, such electrical synapses can be bidirectional, transmitting a
depolarization signal equally well from either cell.
Gap-Junction Channels Connect Communicating Cells at an Electrical Synapse
Electrical transmission takes place at a specialized region of contact between two neurons termed the gap junction. At electrical synapses the separation between two
neurons is much less (3.5 nm) than the normal, nonsynaptic space between neurons (20 nm). This narrow gap is bridged by the gap-junction channels, specialized
protein structures that conduct the flow of ionic current from the presynaptic to the postsynaptic cell (Figure 10-4).
All gap-junction channels consist of a pair of hemichannels, one in the presynaptic and the other in the postsynaptic cell. These hemichannels make contact in the gap
between the two cell membranes, forming a continuous bridge between the cytoplasm of the two cells (Figure 10-4A). The pore of the channel has a large diameter of
around 1.5 nm, and this large size permits small intracellular metabolites and experimental markers such as fluorescent dyes to pass between the two cells.
Each hemichannel is called a connexon. A connexon is made up of six identical protein subunits, called connexins (Figure 10-4B). Each connexin is involved in two sets
of interactions. First, each connexin recognizes the other five connexins to form a hemichannel. Second, each connexin of a hemichannel in one cell recognizes the
extracellular domains of the apposing connexin of the hemichannel of the other cell to form the conducting channel that connects the two cells.
Figure 10-4 A three-dimensional model of the gap-junction channel, based on X-ray and electron diffraction studies.
A. At electrical synapses two cells are structurally connected by gap-junction channels. A gap-junction channel is actually a pair of hemichannels, one in each apposite
cell, that match up in the gap junction through homophilic interactions. The channel thus connects the cytoplasm of the two cells and provides a direct means of ion
flow between the cells. This bridging of the cells is facilitated by a narrowing of the normal intercellular space (20 nm) to only 3.5 nm at the gap junction. (Adapted
from Makowski et al. 1977.)
Electron micrograph: The array of channels shown here was isolated from the membrane of a rat liver. The tissue has been negatively stained, a technique that
darkens the area around the channels and in the pores. Each channel appears hexagonal in outline. Magnification × 307,800. (Courtesy of N. Gilula.)
B. Each hemichannel, or connexon, is made up of six identical protein subunits called connexins. Each connexin is about 7.5 nm long and spans the cell membrane. A
single connexin is thought to have four membrane-spanning regions. The amino acid sequences of gap- junction proteins from many different kinds of tissue all show
regions of similarity. In particular, four hydrophobic domains with a high degree of similarity among different tissues are presumed to be the regions of the protein
structure that traverse the cell membrane. In addition, two extracellular regions that are also highly conserved in different tissues are thought to be involved in the
homophilic matching of apposite hemichannels.
C. The connexins are arranged in such a way that a pore is formed in the center of the structure. The resulting connexon, with an overall diameter of approximately
1.5-2 nm, has a characteristic hexagonal outline, as shown in the electron micrograph in A. The pore is opened when the subunits rotate about 0.9 nm at the
cytoplasmic base in a clockwise direction. (From Unwin and Zampighi 1980.)
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Connexins from different tissues all belong to one large gene family. Each connexin subunit has four hydrophobic domains thought to span the cell membrane. These
membrane-spanning domains in the gap-junction channels of different tissues are quite similar, as are the two extracellular domains thought to be involved in the
homophilic recognition of the hemichannels of apposite cells (Figure 10-4C). On the other hand, the cytoplasmic regions of different connexins vary greatly, and this
variation may explain why gap junctions in different tissues are sensitive to different modulatory factors that control their opening and closing.
For example, most gap-junction channels close in response to lowered cytoplasmic pH or elevated cytoplasmic Ca2+. These two properties serve to decouple damaged
cells from other cells, since damaged cells contain elevated Ca2+ and proton concentrations. At some specialized gap junctions the channels have voltage-dependent
gates that permit them to conduct depolarizing current in only one direction, from the presynaptic cell to the postsynaptic cell. These junctions are called rectifying
synapses. (The crayfish giant motor synapse is an example.) Finally, neurotransmitters released from nearby chemical synapses can modulate the opening of gapjunction channels through intracellular metabolic reactions (see Chapter 13).
How do the channels open and close? One suggestion is that, to expose the channel's pore, the six connexins in a hemichannel rotate slightly with respect to one
another, much like the shutter in a camera. The concerted tilting of each connexin by a few Ångstroms at one end leads to a somewhat larger displacement at the other
end (Figure 10-4B). As we saw in Chapter 7, conformational changes in ion channels may be a common mechanism for opening and closing the channels.
Electrical Transmission Allows the Rapid and Synchronous Firing of Interconnected Cells
Why is it useful to have electrical synapses? As we have seen, transmission across electrical synapses is extremely rapid because it results from the direct flow of
current from the presynaptic neuron to the postsynaptic cell. And speed is important for certain escape responses. For example, the tail-flip response of goldfish is
mediated by a giant neuron (known as Mauthner's cell) in the brain stem, which receives input from sensory neurons at electrical synapses. These electrical synapses
rapidly depolarize the Mauthner's cell, which in turn activates the motor neurons of the tail, allowing the fish to escape quickly from danger.
Electrical transmission is also useful for connecting large groups of neurons. Because current flows across the membranes of all electrically coupled cells at the same
time, several small cells can act coordinately as one large cell. Moreover, because of the electrical coupling between the cells, the effective resistance of the coupled
network of neurons is smaller than the resistance of an individual cell. As we have seen from Ohm's law (∆V = ∆I × R), the lower the resistance of a neuron, the smaller
the depolarization produced by an excitatory synaptic current. Thus, electrically coupled cells require a larger synaptic current to depolarize them to threshold,
compared with the current that would be necessary to fire an individual cell. This property makes it difficult to cause them to fire action potentials. Once this high
threshold is surpassed, however, electrically coupled cells tend to fire synchronously because active Na+ currents generated in one cell are rapidly transmitted to the
other cells.
Thus, a behavior controlled by a group of electrically coupled cells has an important adaptive advantage: It is triggered explosively in an all-or-none manner. For
example, when seriously perturbed, the marine snail Aplysia releases massive clouds of purple ink that provide a protective screen. This stereotypic behavior is
mediated by three electrically coupled, high-threshold motor cells that innervate the ink gland. Once the threshold for firing is exceeded in these cells, they fire
synchronously (Figure 10-5). In certain fish, rapid eye movements (called saccades) are also mediated by electrically coupled motor neurons acting synchronously.
In addition to providing speed or synchrony in neuronal signaling, electrical synapses also may transmit metabolic signals between cells. Because gap-junction channels
are relatively large and nonselective, they readily allow inorganic cations and anions to flow through. In fact, gap-junction channels are large enough to allow moderatesized organic compounds (less than 1000 molecular weight)—such as the second messengers IP3 (inositol triphosphate), cAMP, and even small peptides—to pass from
one cell to the next.
Gap Junctions Have a Role in Glial Function and Disease
Gap junctions are found between glial cells as well as between neurons. In glia the gap junctions seem to mediate both intercellular and intracellular communication.
The role of gap junctions in signaling between glial cells is best observed in the brain, where individual astrocytes are connected to each other through gap junctions,
forming a glial cell network. Electrical stimulation of neuronal pathways in brain slices can trigger a rise of intracellular Ca2+ in certain astrocytes. This produces a wave
of intracellular Ca2+ throughout the astrocyte network,
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traveling at a rate of around 1 µm/ms. These Ca2+ waves are believed to propagate by diffusion through gap-junction channels. Although the precise function of such
Ca2+ waves is not known, their existence clearly suggests that glia may play an active role in signaling in the brain.
Figure 10-5 Electrically coupled motor neurons firing together can produce instantaneous behaviors. The behavior illustrated here is the release of a
protective cloud of ink by the marine snail Aplysia. (Adapted from Carew and Kandel 1976.)
A. Sensory neurons from the tail ganglion form synapses with three motor neurons that project to the ink gland. The motor neurons are interconnected by means of
electrical synapses.
B. A train of stimuli applied to the tail produces a synchronized discharge in all three motor neurons. 1. When the motor neurons are at rest the stimulus triggers a
train of identical action potentials in all three cells. This synchronous activity in the motor neurons results in the release of ink. 2. When the cells are hyperpolarized the
stimulus cannot trigger action potentials, because the cells are too far from their threshold level. Under these conditions the inking response is blocked.
Evidence that gap junctions enhance communication within a single glial cell is found in Schwann cells of the myelin sheath. As we have seen in Chapter 4, successive
layers of myelin are connected by gap junctions, which may serve to hold the layers of myelin together. However, they may also be important for passing small
metabolites and ions across the many intervening layers of myelin, from the outer perinuclear region of the Schwann cell down to the inner periaxonal region. The
importance of these gap-junction channels is underscored by certain neurological genetic diseases. For example, the X chromosome-linked form of Charcot-Marie-Tooth
disease, which causes demyelination, results from single mutations in one of the connexin genes (connexin32) expressed in the Schwann cell. Such mutations prevent
this connexin from forming functional gap-junction channels essential for the normal flow of metabolites in the Schwann cell.
Chemical Synapses Can Amplify Signals
In contrast to the situation at electrical synapses, there is no structural continuity between pre- and postsynaptic neurons at chemical synapses. In fact, at chemical
synapses the region separating the pre- and postsynaptic cells—the synaptic cleft—is usually slightly wider (20-40 nm), sometimes substantially wider, than the
adjacent nonsynaptic intercellular space (20 nm). As a result, chemical synaptic transmission depends on the release of a neurotransmitter from the presynaptic neuron.
A neurotransmitter is a chemical substance that will bind to specific receptors in the postsynaptic cell membrane. At most chemical synapses transmitter release occurs
from presynaptic terminals, specialized swellings of the axon. The presynaptic terminals contain discrete collections of synaptic vesicles, each of which is filled with
several thousand molecules of a specific transmitter (Figure 10-6).
The synaptic vesicles cluster at regions of the membrane specialized for releasing transmitter called active zones. During discharge of a presynaptic action potential Ca2
+
enters the presynaptic terminal through voltage-gated Ca2+ channels at the active zone. The rise in intracellular Ca2+ concentration causes the vesicles to fuse with
the presynaptic membrane and thereby release their neurotransmitter into the synaptic cleft, a process termed exocytosis.
The transmitter molecules then diffuse across the synaptic cleft and bind to their receptors on the postsyn-aptic cell membrane. This in turn activates the receptors,
leading to the opening or closing of ion channels. The resulting ionic flux alters the membrane conductance and potential of the postsynaptic cell (Figure 10-7).
These several steps account for the synaptic delay at chemical synapses, a delay that can be as short as 0.3 ms but often lasts several milliseconds or longer. Although
chemical transmission lacks the speed of electrical synapses, it has the important property of amplification. With the discharge of just one synaptic vesicle, several
thousand molecules of transmitter stored in that vesicle are released. Typically, only two molecules of transmitter are required to open a single postsynaptic ion channel.
Consequently, the action of one synaptic vesicle can open thousands of ion channels in the postsynaptic cell. In this way a small presynaptic nerve terminal, which
generates only a weak electrical current, can release thousands of transmitter molecules that can depolarize even a large postsynaptic cell.
Figure 10-6 The synaptic cleft separates the presynaptic and postsynaptic cell membranes at chemical synapses. This electron micrograph shows the fine
structure of a presynaptic terminal in the cerebellum. The large dark structures are mitochondria. The many round bodies are vesicles that contain neurotransmitter.
The fuzzy dark thickenings along the presynaptic side of the cleft (arrows) are specialized areas, called active zones, that are thought to be docking and release sites
for vesicles. (Courtesy of J. E. Heuser and T. S. Reese.)
Figure 10-7 Synaptic transmission at chemical synapses involves several steps. An action potential arriving at the terminal of a presynaptic axon causes
voltage-gated Ca2+ channels at the active zone to open. The influx of Ca2+ produces a high concentration of Ca2+ near the active zone, which in turn causes vesicles
containing neurotransmitter to fuse with the presynaptic cell membrane and release their contents into the synaptic cleft (a process termed exocytosis). The released
neurotransmitter molecules then diffuse across the synaptic cleft and bind to specific receptors on the post-synaptic membrane. These receptors cause ion channels to
open (or close), thereby changing the membrane conductance and membrane potential of the postsynaptic cell. The complex process of chemical synaptic transmission
is responsible for the delay between action potentials in the pre- and post-synaptic cells compared with the virtually instantaneous transmission of signals at electrical
synapses (see Figure 10-2B). The gray filaments represent the docking and release sites of the active zone.
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Chemical Transmitters Bind to Postsynaptic Receptors
Chemical synaptic transmission can be divided into two steps: a transmitting step, in which the presynaptic cell releases a chemical messenger, and a receptive step, in
which the transmitter binds to the receptor molecules in the postsynaptic cell.
The transmitting process resembles the release process of an endocrine gland, and chemical synaptic transmission can be seen as a modified form of hormone
secretion. Both endocrine glands and presynaptic terminals release a chemical agent with a signaling function, and both are examples of regulated secretion (Chapter
4). Similarly, both endocrine glands and neurons are usually some distance from their target cells. There is one important difference, however. The hormone released by
the gland travels through the blood stream until it interacts with all cells that contain an appropriate receptor. A neuron, on the other hand, usually communicates only
with specific cells, the cells with which it forms synapses. Communication consists of a presynaptic neuron sending an action potential down its axon to the axon
terminal, where the electrical signal triggers the focused release of the chemical transmitter onto a target cell. Thus the chemical signal travels only a small distance to
its target. Neuronal signaling, therefore, has two special features: It is fast and precisely directed.
To accomplish this highly directed or focused release, most neurons have specialized secretory machinery, the active zones. In neurons without active zones the
distinction between neuronal and hormonal transmission becomes blurred. For example, the neurons in the autonomic nervous system that innervate smooth muscle
reside at some distance from their postsynaptic cells and do not have specialized release sites in their terminals. Synaptic transmission between these cells is slower and
more diffuse. Furthermore, at one set of terminals a transmitter can be released at an active zone, as a conventional transmitter acting directly on neighboring cells; at
another locus it can be released in a less focused way as a modulator, producing a more diffuse action; and at a third locus it can be released into the blood stream as a
neurohormone.
Although a variety of chemicals serve as neurotransmitters, including both small molecules and peptides (see Chapter 15), the action of a transmitter in the
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postsynaptic cell does not depend on the chemical properties of the transmitter but rather on the properties of the receptors that recognize and bind the transmitter. For
example, acetylcholine (ACh) can excite some postsynaptic cells and inhibit others, and at still other cells it can produce both excitation and inhibition. It is the receptor
that determines whether a cholinergic synapse is excitatory or inhibitory and whether an ion channel will be activated directly by the transmitter or indirectly through a
second messenger.
Figure 10-8 Neurotransmitters act either directly or indirectly on ion channels that regulate current flow in neurons.
A. Direct gating of ion channels is mediated by ionotropic receptors. This type of receptor is an integral part of the same macromolecule that forms the channel it
regulates and thus is sometimes referred to as a receptor-channel or ligand-gated channel. Many ionotropic receptors are composed of five subunits, each of which is
thought to contain four membrane-spanning α-helical regions (see Chapters 11, 12).
B. Indirect gating is mediated by activation of metabotropic receptors. This type of receptor is distinct from the ion channels it regulates. The receptor activates a GTPbinding protein (G protein), which in turn activates a second-messenger cascade that modulates channel activity. Here the G protein stimulates adenylyl cyclase, which
converts ATP to cAMP. The cAMP activates the cAMP-dependent protein kinase (cAMP-kinase), which phosphorylates the channel (P), leading to a change in function.
(The action of second messengers in regulating ion channels is described in detail in Chapter 13.) The typical metabotropic receptor is composed of a single subunit
with seven membrane-spanning α-helical regions that bind the ligand within the plane of the membrane.
Within a group of closely related animals a given transmitter substance binds to conserved families of receptors and is associated with specific physiological functions.
For example, in vertebrates ACh produces synaptic excitation at the neuromuscular junction by acting on a special type of excitatory ACh receptor. It also slows the
heart by acting on a special type of inhibitory ACh receptor.
The notion of a receptor was introduced in the late nineteenth century by the German bacteriologist Paul Ehrlich to explain the selective action of toxins and other
pharmacological agents and the great specificity of immunological reactions. In 1900 Ehrlich wrote, “Chemical substances are only able to exercise an action on the
tissue elements with which they are able to establish an intimate chemical relationship.… [This relationship] must be specific. The [chemical] groups must be adapted to
one another… as lock and key.” In 1906 the English pharmacologist John Langley postulated that the sensitivity of skeletal muscle to curare and nicotine was caused by
a “receptive molecule.” A theory of receptor function was later developed by Langley's students (in particular, Eliot Smith and Henry Dale), a development that was
based on concurrent studies of enzyme kinetics and cooperative interactions between small molecules and proteins. As we shall see in the next chapter, Langley's
“receptive molecule” has been isolated and characterized as the ACh receptor of the neuromuscular junction
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All receptors for chemical transmitters have two biochemical features in common:
●
They are membrane-spanning proteins. The region exposed to the external environment of the cell recognizes and binds the transmitter from the pre-synaptic
cell.
●
They carry out an effector function within the target cell. The receptors typically influence the opening or closing of ion channels.
Postsynaptic Receptors Gate Ion Channels Either Directly or Indirectly
Chemical neurotransmitters act either directly or indirectly in controlling the opening of ion channels in the postsynaptic cell. The two classes of transmitter actions are
mediated by receptor proteins derived from different gene families.
Receptors that gate ion channels directly, such as the nicotinic ACh receptor at the neuromuscular junction, are integral membrane proteins. Several subunits comprise
a single macromolecule that contains both an extracellular domain that forms the receptor for transmitter and a membrane-spanning domain that forms an ion channel
(Figure 10-8A). Such receptors are often referred to as ionotropic receptors. Upon binding neurotransmitter the receptor undergoes a conformational change that results
in the opening of the channel. The actions of ionotropic receptors, also called receptor-channels or ligand-gated channels, are discussed in greater detail in Chapter 11.
Receptors that gate ion channels indirectly, like the several types of norepinephrine or serotonin receptors at synapses in the cerebral cortex, are macromolecules that
are distinct from the ion channels they affect. These receptors act by altering intracellular metabolic reactions and are often referred to as metabotropic receptors.
Activation of these receptors very often stimulates the production of second messengers, small freely diffusible intracellular metabolites such as cAMP and diacylglycerol.
Many such second messengers activate protein kinases, enzymes that phosphorylate different substrate proteins. In many instances the protein kinases directly
phosphorylate ion channels, leading to their opening or closing. The actions of the metabotropic receptor are examined in detail in Chapter 13.
Ionotropic and metabotropic receptors have different functions. The ionotropic receptors produce relatively fast synaptic actions lasting only milliseconds. These are
commonly found in neural circuits that mediate rapid behaviors, such as the stretch receptor reflex. The metabotropic receptors produce slower synaptic actions lasting
seconds to minutes. These slower actions can modulate behavior by altering the excitability of neurons and the strength of the synaptic connections of the neural
circuitry mediating behavior. Such modulatory synaptic pathways often act as crucial reinforcing pathways in the process of learning.
Selected Readings
Bennett MV. 1997. Gap junctions as electrical synapses. J Neurocytol 26:349–366.
Eccles JC. 1976. From electrical to chemical transmission in the central nervous system. The closing address of the Sir Henry Dale Centennial Symposium. Notes
Rec R Soc Lond 30:219–230.
Furshpan EJ, Potter DD. 1959. Transmission at the giant motor synapses of the crayfish. J Physiol (Lond) 145:289–325.
Goodenough DA, Goliger JA, Paul DL. 1996. Connexins, connexons, and intercellular communication. Ann Rev Biochem 65:475–502.
Jessell TM, Kandel ER. 1993. Synaptic transmission: a bidirectional and a self-modifiable form of cell-cell communication. Cell 72(Suppl):1–30.
Unwin N. 1993. Neurotransmitter action: opening of ligand-gated ion channels. Cell 72(Suppl):31–41.
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