Download Overview of Synaptic Transmission

10
Overview
Overview of
of Synaptic
Synaptic Tr,
Transmission
Syn.apsesAre Either Electrical or Chemical
Electrical Syn.apsesProvide Instantaneous Signal
1I:ansmission
Gap-JunctionChannelsConnectCommunicating Cells at
an ElectricalSynapse
ElectricalTransmissionAllows the Rapid and
SynchronousFiring of InterconnectedCells
Gap JunctionsHave a Role in Glial Function and Disease
Chemical SynapsesCan Amplify Signals
ChemicalTransmittersBind to PostsynapticReceptors
PostsynapticReceptorsGate Ion ChannelsEither Directly
or Indirectly
W
HATGIVESNERVE
CELLStheir 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 mechanismsfor signaling betweenneurons. The point at which one neuron
communicates with another is called a synapse,and
synaptic transmission is fundamental to many of the
processeswe consider later in the book, such as perception, voluntary movement, and learning.
Theaverageneuronformsabout 1000synapticconnections and receives even more, perhaps as many as
10,000connections. The Purkinje cell of the cerebellum
receivesup to 100,000inputs. 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 pblsticityin 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 themselvesto 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 producemore complexbehaviors.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 synapsesalso serve to amplify neuronal signals,sothat evena smallpresynapticnerveterminal can alter the responseof a large postsynaptic cell.
Becausechemical 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 synapsewas introduced at the turn of the century by Charles Sherrington to describe the specialized
zone of contact at which one neuron communicateswith
another; this site had first been described histologically
(at the level of light microscopy) by Ram6n y Cajal. Initially, all synapseswere thought to operate by means of
electrical transmission. In the 1920s, however, Otto
Loewi showed that acetylcholine (ACh), a chemicalcompound, conveys signals from the vagus nerve to the
176
Partm / ElementaryInteractionsBetweenNeurons:SynapticThansmission
Table 10-1 Distinguishing Properties of Electrical and Chemical Synapses
Type of
synapse
Distance between
pre- and
postsynaptic cell
membranes
Cytoplasmic
continuity
between pre- and
postsynaptic cells
Electrical
3.5nm
Chemical
20-40nm
Ultrastructural
components
Agent of
transmission
Synaptic
delay
Direction of
transmission
Yes
Gap-junction
channels
Ion current
Vtrtually
absent
Usually
bidirectional
No
Presynaptic
vesicles and
active zones;
postsynaptic
receptors
Chemical
transmitter
Significant:
at least 0.3
IDS,usually
1-5 IDS
or longer
Unidirectional
heart. Loewi's discovery in the heart provoked considerable debate in the 193Osover how chemical signals
could generateelectrical activities at other synapses,including nerve-muscle synapses and synapses in the
brain.
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
substancethat in turn initiates current flow in the postsynaptic cell.
A Current flow at electrical synapses
When physiological techniques improved in the
19508and 1960sit becameclear that both forms of transmission exist. Although most synapsesuse a chemical
transmitter, some operate purely by electrical means.
Oncethe fine structure of synapses was made visible
with the electron microscope, chemical and electrical
synapseswere found to have different morphologies. At
chemical synapsesneurons are separatedcompletely 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
B Current flow at chemical synapses
I
Presyneptjc
Postsynaptic
Figure10-1 Currentflows differently at electricaland chemical synapses.
A. At an electrical synapsesome of the current injected into a
presynapticcell escapesthrough resting ion channelsin the
cell membrane.However, some current also flows into the
postsynapticcell through specializedion channels.called gapjunction channels,that connect the cytoplasm of the pre- and
postsynapticcells.
B. At chemical synapsesall of the injected current escapes
through ion channelsin the presynapticcell. However,the resulting depolarizationof the cell activates the releaseof neurotransmitter molecules packagedin synaptic vesicles (open circlesl, which then bind to receptors on the postsynapticcell.
This binding opens ion channels,thus initiating a change in
membrane potential in the postsynapticcell.
Chapter10I Overviewof SynapticTransmission 177
I
A Experimentalsetup
PresYl18ptic neuron:
Ieter8I gie~ fiber
Current
Injection
Recordng
----
Iecording
Cutr8nt~
injection
Figure 10-2 Electrical synaptic transmission was first
demonstrated to occur at the giant motor synapse in the
crayfish. (Adaptedfrom Furshpanand Potter 1957 and 1959.)
A. The presynapticneuron is the lateral giant fiber running
down the nerve cord. The postsynaptic neuron is the motor
fiber.which projectsfromthe cell bodyin the ganglionto the
periphery.The electrodes for passing current and for recording
voltage are placed within both the p(f~ and postsynapticcells.
B. Transmissionat an electrical synapse is virtually instant&neous-the postsynapticresponsefollows presynapticstimulation in a fraction of a millisecond.The dashed line shows how
the responsesof the two cells correspondin time. In contrast.
at chemical synapsesthere ia a delay between the pre- and
postsynaptic potentials (see Figure 1~7).
j into the presynaptic cell to elicit a signal (Figure to-t).
external membrane of the postsynaptic ceIL which has a
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At both types of synapses the current flows outward
acrossthe 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 (seeChapter 8).
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 to-tA). H 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.Uttle or no current crossesthe
high resistance(Figure 10-1B).Instead, the action potential in the presynaptic neuron initiates the release of a
chemical transmitter, which diffuses acrossthe synaptic
cleft to interact with receptors on the membrane of the
postsynaptic cell. Receptor activation causesthe cell either to depolarize or to hyperpolarize.
Electrical Synapses Provide Instantaneous
Signal Transmission
At electrical synapses the current that depoJarizesthe
postsynaptic cell is generated directly by the voltagegated 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 becausea small cell
has a higher input resistance(RiD)than a Iarsecell ArnI,
178
Part
m/ ElementaryinteractiON BetweenNeurons:Synaptic Transmission
~
~
~
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Current pulse to
L. presyneptic cell
Volt8ge recorded
\... In presynepticcell
Agur. 10-3 Electrical transmission is graded and occurs
even when the currents In the presynaptic cell are below
the threshold for an ection potential. This can be demonstrated by depolarizingthe presynapticcell with a small outward current pulse. Current is passed by one electrode while
the membranepotential is recorded with a second electrode.
A subthresholddepolarizingstimulus causes a passive depolarization In the presynapticand postsynapticcells. (Outward,
depolarizingcurrent is indicated by upward deflection.)
according to Ohm's law (I1V" tJ x Rjn),will undergo a
greater voltage change (11V) in response to a given
presynaptic current (tJ).
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 to-2A). An action potential generated in
the presynaptic fiber produces a depolarizing postsynaptic potential that is often large enough to discharge an action potential. The lIltency-the time between the presynaptic spike and the postsynaptic
potential-is remarkably short (Figure to-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
subsequentgating 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 p0tential 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 presynaptic 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 releasetransmitter.
Most electrical synapseswill transmit both depolarizing and hyperpolarizing currents. A presynaptic
action potential that has a large hyperpolarizing
afterpotential will produce a biphasic (depolarizinghyperpolarizing) changein potential in the postsynaptic
cell. Transmission at electrical synapsesis similar to the
passiveelectrotonic propagation of subthreshold electrical signals along axons (seeChapter 8) and therefore is
often referred to as electrotonictransmission.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
synapsesdepends 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 ChannelsConnectCommunicating
Cells at an Electrical Synapse
Electrical transmission takes place at a specialized region of contact between two neurons termed the gap
junction. At electrical synapsesthe separation between
two neurons is much less (3.5 nm) than the normal, nonsynapticspace between neurons (20 nm). This narrow
gap is bridged by the gap-junctiondulnnels,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(Figure10-4B).Each connexin is involved in two
sets of interactions. First, each connexin recognizesthe
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 connectsthe two cells.
~
Chapter 10 / Overview of SynapticTransmission
179
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extracellular
space
Ch8meI formed
bvporesin
88d1 membr8ne
.
6 connexin subunits
1 connexon (hemich8nnell
&ch 01 the 15connexins
has .. membr8ne-spenning
regions
Cytopllsmic loops
for regulation
ExtraceIIulir
Ip8C8
,
Extracellular loops for
hemophilic interactions
Figure 10-4 A three-dimensionalmodelof
the gap-junction channel, based on X-ray
and electron diffraction studies.
A. At electrical synapsestwo cells are structurally connected by gap-junctionchannels.
A gap-junctionchannel is actuallya pair of
hemichannels,one in each apposite cell, that
match up in the gap junction through
homophilicinteractions.The channelthus 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
narrowingof the normal intercellularspace
(20 nm) to only 3.5 nm at the gap junction.
(Adaptedfrom Makowski et al. 1977.)
Electron micrograph: The arrayof channels
shown here was isolated from the membrane
of a rat liver.The tissue has been negatively
stained, a technique that darkensthe area
aroundthe channelsand in the pores. Each
channelappearshexagonalin outline. Magnification x 307,800. (Courtesyof 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 membranErSpanning regions. The amino acid sequences of gapjunction 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.)
180
Part ill / ElementaryInteractionsBetweenNeurons: Synaptic Transmission
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 gapjunction channelsof different tissuesare quite similar, as
are the two extracellular domains thought to be involved in the homophilic recognition of the hemichannels of apposite cells (Figure lo-4C). On the other hand,
the cytoplasmic regions of different connexins vary
greatly, and this variation may explain why gap junctions in different tissuesare 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 CaH. These two properties serve to decouple
damaged cells from other cells, since damaged cells contain elevated ea2+ and proton concentrations. At some
specialized gap junctions the channels have voltagedependent gatesthat 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 synapsescan modulate the opening of
gap-junction channels through intracellular metabolic
reactions (seeChapter 13).
How do the channels open and close?One suggestion is that, to exposethe 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 Angstroms at
one end leads to a somewhat larger displacement at the
other end (Figure lO-4B). As we saw in Chapter 7, conformational changesin 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 synap~? As we have
seen, transmission across electrical synapses is extremely rapid becauseit 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
synapsesrapidly depolarize the Mauthner's cell, which
in turn activates the motor neurons of the tail, allowing
the fish to escapequickly from danger.
Electrical transmission is also useful for connecting
large groups of neurons. Becausecurrent flows across
the membranes of all electrically coupled cells at the
same time, several small cells can act coordinately as
one large cell. Moreover, becauseof the electrical coupling between the cells, the effective resistanceof the
coupled network of neurons is smaller than the resistance of an individual cell. As we have seenfrom Ohm's
law (AV = AI X R), the lower the resistanceof 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
necessaryto 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 becauseactive
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 releasesmassive 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 exceededin 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
metabolicsignals 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 channelsare large enough
to allow moderate-sized organic compounds (less than
1000 molecular weight~ch
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 seemto 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 astrocytenet-
Chapter 10 / Overview of SynapticTransmission
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
AplysiB.(Adaptedfrom Carew and Kandel
1976.)
A. Sensoryneuronsfrom the tail ganglion
form synapseswith three motor neurons
that project to the ink gland.The motor
neuronsare interconnectedby means of
electricalsynapses.
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.
A Neural circuit of the inking response
B Motor cell responses to tail stimulation
1 Cellsat rest
R8IeIse
of Ink
A
c
2 Cells hyperpolarized
........
ofink
181
182
Part
ill / ElementaryInteractionsBetweenNeurons: Synaptic Transmission
work, traveling at a rate of around 1 JLn'l/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 suggeststhat glia may play an active role
in signaling in the brain.
Evidence that gap junctions enhance communication within a single glial cell is found in Schwann cells
of the myelin sheath.As we have seenin Chapter 4, successivelayers of myelin are connectedby gap junctions,
which may serve to hold the layers of myelin together.
However, they may also be important for passing small
metabolitesand ions acrossthe 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 CharcotMarie-Tooth disease, which causes demyelination,
results from single mutations in one of the connexin
genes(connexin32)expressedin 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.
termed exocytosis.
The transmitter molecules then diffuse across the
synaptic cleft and bind to their receptorson the postsynaptic cell membrane.This in turn activatesthe 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 speedof 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. lYPically, 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 generatesonly a weak electrical current,
can releasethousands of transmitter molecules that can
depolarize even a large postsynaptic 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
synapsesthe region separating the pre- and postsynaptic cells-the synaptic cleft-is usually slightly wider
(20-40 nm), sometimessubstantially 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 neurotransmitteris a chemical substancethat
will bind to specific receptors in the postsynaptic cell
membrane. At most chemical synapses,transmitter release occurs from presynaptic termiruzls, specialized
swellings of the axon. The presynaptic terminals contain
discrete collections of synapticvesicles,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 voltagegated Ca2+channelsat 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
~
Figure 10-8 The synaptic cleft separates the presynaptic
and postsynaptic cell membranes at chemical synapses.
This electron micrographshows 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 specializedareas,called active zones,that are thought to be docking and releasesites for
vesicles. (Courtesyof J. E. Heuser and T. S. Reese.)
r
Chapter 10 / Overview of SynapticTransmission
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Rgure 10-7 Synaptic transmission at chemical synapses involves several steps. An action potential arrivingat the terminal of a presynapticaxon causes voltage-gatedCa2+channels
at the active zone to open. The influx of Ca2+producesa high
concentrationof Ca2+near the active zone. which in tum
causesvesicles containing neurotransmitterto fuse with the
presynapticcell membraneand releasetheir contents into the
synapticcleft (a process termed exocytosis).The released
neurotransmittermolecules then diffuse acrossthe synaptic
Chemical Transmitters Bind
to Postsynaptic Receptors
Chemical synaptic transmission can be divided into two
steps: a transmitting step, in which the presynaptic cell
releasesa chemical messenger,and a receptivestep, in
which the transmitter binds to the receptor molecules in
the postsynaptic cell.
The transmitting process resembles the release
processof an endocrine gland, and chemical synaptic
transmission can be seenas a modified form of hormone
secretion.80th endocrine glands and presynaptic terminals releasea 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 communicatesonly with specific cells, the cells with which it
forms synapses.Communication consistsof a presynaptic neuron sending an action potential down its axon to
the axon terminal, where the electrical signal triggers
cleft and bind to specific receptors on the post-synapticmembrane.These receptorscause ion channelsto open (or close).
thereby changingthe membraneconductanceand membrane
potential of the postsynapticcell. The complex processof
chemical synaptic transmissionis responsiblefor the delay between action potentials in the pre- and post-synapticcells ~
pared with the virtually instantaneoustransmissionof signalsat
electrical synapses(see Figure 10-28).The gray filaments rep-
resentthe dockingandreleasesitesof the activezone.
the focused releaseof the chemical transmitter onto a
targetcell.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 becomesblUrred. 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 releasedat an active zone, as
a conventional transmitter acting directly on neighboring cells; at another locus it can be releasedin a less focused way as a modulator, producing a more diffuse action; and at a third locus it can be releasedinto the blood
stream as a neurohormone.
Although a variety of chemicals serve as neurotransmitters, including both small molecules and peptides (seeChapter 15), the action of a transmitter in the
~
184
Part ill / ElementaryInteractions BetweenNeurons: Synaptic Transmission
A Directgating
B Indirect gating
Receptor Pore
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Figure10-8 Neurotransmittersact either directly or indirectly on ion channelsthat regulatecurrent 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-<:hannel or ligand-gated
channel. Many ionotropic receptors are composed of five subunits, each of which is thought to contain four membranespanning a-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
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.
Within a group of closely related animals a given
transmitter substancebinds 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
it regulates. The receptor activates a GTP-binding protein (G
protein), which in tum 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 a-helical regions that bind the
ligand within the plane of the membrane.
nineteenth century by the German bacteriologist Paul
Ehrlich to explain the selectiveaction of toxins and other
pharmacological agents and the great specificity of immunological reactions.In 1900Ehrlich wrote, "Chemical
substancesare only able to exercisean action on the tissue
elementswith which they areable to establishan intimate
chemical relationship. . . . [This relationship] must be
specific. The [chemical] groups must be adapted to one
another. . . as lock and key." In 1906the English pharmacologistJohnLangley 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 basedon
concurrent studies of enzyme kinetics and cooperative
interactions between small molecules and proteins. As
we shall seein the next chapter,Langley's "receptive molecule" hasbeenisolated and characterizedas the ACh receptor of the neuromuscularjunction.
Chapter 10 / Overview of SynapticTransmission
All receptorsfor chemicaltransmittershave two
biochemicalfeaturesin common:
1. Theyare membrane-spanning proteins. The region
exposedto the external environment of the cell recognizes and binds the transmitter from the presynaptic cell.
2 They carry out an effector function within the target cell. The receptors typically influence the opening or closing of ion channels.
lions 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.
Eric
Eric R.
R. Kandel
Kandel
Steven
StevenA.
A. Siegelbaum
Siegelbaum
PostsynapticReceptorsGateIon 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 classesof 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 receptorchannels or ligand-gated channels, are discussed in
greater detail in Chapter 11.
Receptorsthat gate ion channels indirectly, like the
several types of norepinephrine or serotonin receptors
at synapsesin 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 secondmessengers,small freely diffusible
intracellular metabolites such as cAMP and diacylglyceroL Many such second messengersactivate protein kinases,enzymes that phosphorylate different substrate
proteins. In many instancesthe protein ldnases 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.
Theseare commonly found in neural circuits that mediate rapid behaviors, such as the stretch receptor reflex.
The metabotropic receptorsproduce slower synaptic ac-
185
185
Selected Readings
Bennett MY. 1997. Gap junctions as electrical synapses.
J Neurocytol 26:349-366.
Eccles Je. 1976. From electrical to chemical transmission in
the central nervous system. The closing address of the Sir
Henry Dale Centennial Symposium. Notes Rec R Sac
Lond 30-.219-230.
Furshpan BI, Potter DD. 1959.Thmsmission at the giant motor synapsesof the crayfish. J Physiol (Lond) 145:289-325.
Goodenough DA, Go1iger JA, Paul DL. 1996. Connexins,
connexons, and intercellular communication. Ann Rev
Biochem 65:475-502.
Jesse1l'I'M, Kandel ER. 1993. Synaptic transmission: a bidirectional and a self-modifiable form of cell-cell communication. Ce1l72(Suppl):1-30.
Unwin N. 1993.Neurotransmitter action: opening of ligandgated ion channels. Ce1l72(Suppl):31-41.
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