Download resting membrane potential

Chapter 13
Signal Transduction
Mechanisms: I.
Electrical and
Synaptic Signaling
in Neurons
Lectures by
Kathleen Fitzpatrick
Simon Fraser University
© 2012 Pearson Education, Inc.
Signal Transduction Mechanisms:
I. Electrical and Synaptic Signaling in
Neurons
• Cell membranes can regulate the flow of ions between
the interior and exterior of the cell
• The most dramatic example of regulation of the
electrical properties of cells is the nerve cell or neuron
• Nerve cells have special mechanisms for using
electrical potentials to transmit information over long
distances
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Neurons
• Almost all animals have a nervous system in
which impulses are transmitted along the
specialized plasma membranes of nerve cells
• Vertebrates have a central nervous system
(CNS), consisting of the brain and spinal
cord, and a peripheral nervous system (PNS),
which comprises other sensory or motor
components
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Cells of the nervous system
• The nervous system has two main types of
cells
– Neurons send and receive electrical impulses
(nerve impulses)
– Glial cells encompass a variety of cell types
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Neurons
• Sensory neurons are a diverse group of cells
specialized for the detection of stimuli
• Motor neurons transmit signals from the CNS to
the muscles and glands with which they make
connections (innervate)
• Interneurons process signals and transmit
information between parts of the nervous system
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Glial cells
• Microglia fight infections and remove debris
• Oligodendrites and Schwann cells form the
insulating myelin sheath around neurons of the
CNS and peripheral nerves
• Astrocytes control access of blood-borne
components into the extra-cellular fluid around
the nerve cells forming the blood-brain barrier
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Neurons Are Specially Adapted for the
Transmission of Electrical Signals
• The cell body of a neuron is similar to that of
other cells, and includes the nucleus and other
endomembrane components
• Neurons also contain branches called processes
• Processes that receive signals are dendrites
and those that conduct signals are axons
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Axons
• The cytosol within an axon is called axoplasm
• Many vertebrate axons are surrounded by a
discontinuous myelin sheath
• The sheath insulates the segments of axon
separating the nodes of Ranvier
• A nerve is a tissue composed of bundles of
axons
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Motor neurons
• A motor neuron has multiple branched dendrites
and a single axon, which is much longer than
the dendrites
• The branches terminate in structures called
synaptic boutons (terminal bulbs, or synaptic
knobs)
• The boutons transmit the signal to the next cell,
a neuron, muscle, or gland cell
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Synapses
• The junction between a nerve cell, gland, or
muscle cell is called a synapse
• For neuron-to-neuron junctions, synapses occur
between an axon and a dendrite, but they can
also occur between two dendrites
• Typically, neurons make synapses with other
neurons, at the ends of axons and along their
length as well
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Figure 13-1
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Figure 13-1A
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Figure 13-1B
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Video: Neuron structure
Right click on animation / Click play
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Understanding Membrane Potential
• Membrane potential is a fundamental
property of all cells
• Cells at rest normally have excess negative
charge on the outside and positive charge on
the inside of the cell
• The resulting electrical potential is called the
resting membrane potential
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The squid giant axon
• The very large squid giant axon has been
used for studies of nerve transmission since the
1930s
• It’s large size allows for easy insertion of
microelectrodes to measure and control
electrical potentials
• The resting membrane potential can be
measured
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Figure 13-2
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Figure 13-3A
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Resting membrane potential
• Electrodes compare the ratio of negative to
positive charge inside and outside the cell
• The resting membrane potential is about –
60mV for the squid giant axon
• Nerve, muscle, and certain other cell types
exhibit electrical excitability
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Electrically excitable cells
• In electrically excitable cells, certain stimuli
trigger a rapid set of changes in membrane
potential
• This is known as an action potential
• During the action potential the membrane
potential changes from negative to positive
and then back again in a very short time
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Measuring changes in membrane
potential
• Microelectrodes can be used to measure
changes in the membrane potential
• The stimulating electrode is connected to a
power source and inserted into the axon some
distance from the recording electrode
• A brief impulse from the stimulating electrode
depolarizes the membrane, measured at the
recording electrode
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Figure 13-3B
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The Resting Membrane Potential Depends
on Differing Concentrations of Ions Inside
and Outside the Neuron and on the
Selective Permeability of the Membrane
• The cytosol and extracellular fluid of a cell contain
different compositions of anions and cations
• Extracellular fluid contains dissolved salts, mostly
sodium chloride
• The cytosol contains potassium as its main cation
due to the action of the Na+/K+ pump
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Potassium ions and the membrane
potential
• The uneven distribution of potassium ions inside
and outside the cell is the potassium ion gradient
• Because of this gradient, potassium ions will tend
to diffuse out of the cell toward the region of
lower concentration
• Ions in solution are present in pairs, one negative
and one positive (electroneutrality)
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Counterions
• For any given ion, there must be an oppositely
charged ion in the solution
• The oppositely charged ion is called the
counterion
• In the cytosol, potassium (K+) ions serve as
counterions for the trapped anions; outside the
cell, Na+ is the main cation with Cl– as its
counterion
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Electrical potential
• A solution must have an equal number of positive
and negative charges overall, but they can be
unevenly distributed, with one region more positive
and another more negative
• Even when separated, they will tend to flow back
toward each other (electric potential, or voltage)
• When the oppositely charged ions are moving
toward each other, current is flowing, measured in
amperes (A)
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Resting potential forms as a result of ionic
compositions inside and outside the cell
• Some types of potassium channels in the plasma
membrane allow K+ to diffuse out of the cell
• As K+ leaves the cytosol, increasing numbers of
anions are left behind without counterions
• Excess negative charge accumulates outside the
cell and excess positive charge accumulates
outside, resulting in the membrane potential
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Figure 13-4
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Figure 13-4A
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Figure 13-4B
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Equilibrium
• K+ diffuses out of cell down its gradient, but
eventually the gradient is balanced by the K+
electrical potential and net movement of K+ stops
• When a chemical gradient is balanced by an
electrical potential, it is called electrochemical
equilibrium
• The membrane potential at the point of equilibrium
is known as an equilibrium (or reversal)
potential
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The Nernst Equation Describes the
Relationship Between Membrane
Potential and Ion Concentration
• The Nernst equation describes the
mathematical relationship between an ion
gradient and the equilibrium potential that will
form when the membrane is permeable only
to that ion
• .
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The Nernst equation
• The Nernst equation can be expressed as
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The Na+/K+ pump
• The Na+/K+ pump continually pumps sodium ions
out of the cell to compensate for the small
amount of leakage of sodium into the cell
• At the same time, potassium is carried inward
• On average, three sodium are transported
inward for every two potassium ions transported
outward
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Steady-State Concentrations of Common
Ions Affect Resting Membrane Potential
• Equation 13-2 is not complete because it doesn’t
account for the effects of anions
• Because of the unequal distributions of Na+, K+,
and Cl– across the membrane, each has a
different impact on the membrane potential
• Each ion diffuses down its electrochemical
gradient and affects the membrane potential
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Figure 13-5
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Figure 13-5A
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Figure 13-5B
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Figure 13-5C
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Effect of ions on membrane potential
• K+ tends to diffuse out of the cell, making the
membrane potential more negative
• Na+ tends to flow into the cell, driving the
potential in the positive direction, causing
depolarization
• Cl– tends to diffuse into the cell but is repelled by
the negative membrane potential, so enters
along with positive ions
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Increased membrane permeability to
Cl– decreases excitability
• Increasing the membrane permeability to
chloride has two effects, and both decrease
neuronal excitability
– The net entry of chloride ions (without a matching
cation) causes hyperpolarization (membrane
potential is more negative)
– When the membrane becomes permeable to
sodium, some chloride will also enter
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The Goldman Equation Describes the
Combined Effects of Ions on Membrane
Potential
• Even in the resting state the cell is a little
permeable to sodium, chloride, and potassium ions
• The Nernst equation doesn’t account for leakage
of sodium and chloride into the cell; it deals with
just one ion at a time
• It is helpful to consider the steady-state ion
movements across the membrane
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Steady-state movement of ions across
the plasma membrane
• A membrane permeable only to K+ will have a
membrane potential equal to the equilibrium
potential for K+
• If the membrane is also slightly permeable to
Na+, the membrane potential will be partially
depolarized as Na+ leaks into the cell
• There is now less restraint on K+ leaving the cell,
so K+ diffuses outward, balancing the inward
movement of Na+
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Figure 13-6
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Figure 13-6A
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Figure 13-6B
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Goldman, Lloyd, and Katz
• These were the first researchers to describe
how gradients of several different ions each
contribute to a membrane potential
• Their equation, known as the Goldman
equation, is
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Goldman equation
• The Goldman equation, unlike the Nernst
equation, includes terms for permeability of the
ions involved
• In this case PK, Pna, and PCl are the relative
permeabilities for each ion
• Except under special circumstances, the
contribution of other ions to membrane potential
is negligible
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An example of the Goldman equation
• To estimate resting membrane potential in a
squid axon, we use known steady-state
concentrations and relative permeabilities of the
three ions
• K+ can be assigned a permeability value of 1.0
and the others are determined relative to that
• The relative permeability of Na+ is 4% (0.04) and
Cl– is 45% (0.45)
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An example of the Goldman equation
• Using the relative permeabilities and the
concentrations of the ions from Table 13-1,
one can estimate resting potential of the
squid axon
• This comes to –60.3 mV
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Table 13-1
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Nernst and Goldman equations
• When the relative permeability of one of the ions
is very high, the Goldman equation reduced to
the Nernst equation for that ion
• For instance, if we ignore the effect of Cl–, as we
can when Pna → PK
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Electrical Excitability
• The unique feature of electrically excitable cells is
their response to depolarization
• Excitable cells respond with an action potential
• Excitable cells have voltage-gated channels in
their plasma membranes
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Ion Channels Act Like Gates for the
Movement of Ions Through the Membrane
• Ion channels: integral membrane proteins
that form ion-conducting pores in the lipid
bilayer
• Voltage-gated ion channels respond to
changes in the voltage across a membrane
• Voltage-gated Na+ and K+ channels are
responsible for the action potential
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Other ion channels
• Ligand-gated ion channels open when a
ligand binds to the channel
• Other channels contribute to the steady-state
ionic permeability of membranes
• These leak channels allow cells to be
somewhat permeable to cations
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Patch Clamping and Molecular
Biological Techniques Allow the Activity
of Single Ion Channels to Be Monitored
• Patch clamping, or single-channel recording,
records currents passing through individual
channels
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Figure 13-7
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Patch Clamping
• An amplifier keeps the membrane at a fixed
membrane potential despite changes in its
electrical properties
• Then the voltage clamp measures tiny changes
in current flow through individual channels
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Conductance
• Conductance is an indirect measure of the
permeability of a channel when a particular
voltage is applied
• It is the inverse of resistance
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Specific Domains of Voltage-Gated
Channels Act as Sensors and
Inactivators
• Voltage-gated potassium channels are multimeric
proteins, composed of four protein subunits
• Voltage-gated sodium channels are large
monomeric proteins with four separate domains
• In both types of channels each domain or subunit
contains six transmembrane -helices
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Figure 13-8A
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Channel specificity
• The size of the central pore and the way it
interacts with an ion gives the channel its
specificity
• Oxygen atoms in the amino acids at the center of
the channel are positioned to interact with ions as
they move through the selectivity filter
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Channel gating
• Voltage-gated sodium channels can open
rapidly in response to a stimulus and then
close again; channel-gating
• The open or closed state is all-or-none; the
channels are not partially open
• The fourth subunit, S4, acts as a voltage
sensor, responding to changes in potential
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Figure 13-8C
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Channel inactivation
• Most voltage-gated channels adopt a second
type of closed state, channel inactivation
• When a channel is inactivated it cannot reopen
immediately, even if stimulated to do so
• Inactivation is caused by part of the channel
called the inactivation particle that inserted in the
opening of the channel
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Figure 13-9
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The Action Potential
• The coordinated opening and closing of ion
channels leads to an action potential
• The giant axon of the squid has been
important in the study of action potential
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Action Potentials Propagate
Electrical Signals Along an Axon
• Depolarization that brings the membrane to the
threshold potential initiates an action potential
• An action potential is a brief but large electrical
depolarization and repolarization of the neuronal
plasma membrane
• It is caused by inward movement of sodium and
subsequent outward movement of potassium
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Action Potentials
• Movement of sodium and potassium ions
during the action potential are controlled by
the opening and closing of voltage-gated
channels
• Once the action potential is initiated it will
travel along the membrane away from the
origin by a process called propagation
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Action Potentials Involve Rapid Changes
in the Membrane Potential of the Axon
• Development and propagation of an action
potential (all within a few milliseconds)
– Membrane potential rises dramatically to about
+40 mV
– It then falls slowly to about –75 mV (undershoot,
or hyperpolarization)
– It stabilizes again at the resting potential of about
–60 mV
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Action Potentials Result from the
Rapid Movement of Ions Through
Axonal Membrane Channels
• In a resting neuron the voltage-dependent
channels are usually closed
• Because of leakiness to K+, the cell is about 100
times more permeable to K+ than to Na+
• When a region of the nerve cell is slightly
depolarized, some of the Na+ channels open
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Rapid movement of ions through axonal
membrane channels
• The increased flow of Na+ through the channels
increases membrane depolarization
• Increasing depolarization opens more channels,
causing more Na+ to flow, etc.
• This positive feedback loop is called the Hodgkin
cycle
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Subthreshold Depolarization
• When the membrane is depolarized by a small
amount, the membrane potential recovers
because of K+ movement through leak channels
• In this case no action potential occurs
• Levels of depolarization too small to initiate an
action potential are called subthreshold
depolarizations
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The Depolarizing Phase
• When the membrane is depolarized past the
threshold potential a significant number of Na+
channels begin activating
• The membrane potential shoots upward rapidly
• It peaks at about +40 mV
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Figure 13-10
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Figure 13-10A
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Figure 13-10B
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The Repolarizing Phase
• Once the membrane potential has risen to its peak the
membrane quickly repolarizes
• This is due to inactivation of sodium channels and
opening of voltage-gated potassium channels
• The inactivated sodium channels remain closed until the
membrane potential is negative again
• The cell repolarizes as K+ leaves the cell
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The Hyperpolarizing Phase
(Undershoot)
• At the end of an action potential most neurons
show a transient hyperpolarization or undershoot
• The membrane potential temporarily drops below
the resting potential. This occurs because of
increased potassium permeability.
• As the voltage-gated potassium channels close,
the membrane potential returns to normal
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The Refractory Periods
• For a few milliseconds after an action potential, it
is impossible to trigger a second one
• This is the absolute refractory period, when
sodium channels are inactivated and cannot open
by depolarization
• During undershoot, sodium channels can open
again but potassium channels are open, too
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Refractory Periods
• Potassium leak channels and voltage-gated
channels are open, driving the membrane
potential down
• This is well below the threshold for triggering
another action potential
• This time is called the relative refractory
period
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Changes in Ion Concentrations Due
to an Action Potential
• During an action potential, cellular concentrations
of Na+ and K+ hardly change at all
• The ions involved are a small fraction of the total
ions in the cell
• Intense neuronal activity can lead to significant
changes in ion concentration
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Action Potentials Are Propagated Along
the Axon Without Losing Strength
• Depolarization that occurs in one place along a
membrane spreads to adjacent regions through
passive spread of depolarization
• As it spreads away from the origin it decreases in
magnitude, so signals cannot travel far by this
means
• To go farther, the action potential must be
propagated, actively generated without fading as it
moves
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Figure 13-11
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Transmission of a signal
• Incoming signals are transmitted to a neuron at
points of contact called synapses
• Incoming signals depolarize the dendrites and
the depolarization spreads passively over the
membrane to the base of the axon, the axon
hillock
• This is where action potentials are most easily
generated
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Propagation of an action potential in
a nonmyelinated nerve cell
• Stimulation of a resting membrane results in
depolarization and an inward rush of Na+ (1)
• Membrane polarity is temporarily reversed
and this spreads (2)
• Nearby depolarization is above a threshold,
and results in an inward movement of Na+ (3)
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Figure 13-12, Steps 1-3
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Propagation of an action potential
(continued)
• The original region on the membrane becomes
permeable to K+ ions, which rush out of the cell,
and return the membrane to its resting state (4)
• Meanwhile, depolarization has spread farther,
initiating the same sequence of events there (5)
• The propagation of these events is a propagated
action potential or nerve impulse
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Figure 13-12, Steps 4-5
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The Myelin Sheath Acts Like an Electrical
Insulator Surrounding the Axon
• Most vertebrate axons are surrounded by many
concentric layers of membrane, forming a
discontinuous myelin sheath
• It is formed by oligodendrites in the CNS and
Schwann cells in the PNS
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Figure 13-13
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Figure 13-13A
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Figure 13-13C
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Consequences of myelination
• Myelination decreases the ability of the neuronal
membrane to retain electric charge (i.e.,
capacitance)
• Nerve impulses can spread farther and faster
than in the absence of myelination
• The action potential must still be renewed; this
happens at nodes of Ranvier
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Action potentials are renewed at nodes
of Ranvier
• Nodes of Ranvier are spaced closely enough to
ensure the action potential at one node can
trigger one in the next node
• Action potentials jump from one node to the next,
called saltatory propagation, more rapid than
continuous propagation
• Nodes of Ranvier are highly organized structures
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Figure 13-13B
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Figure 13-14, Steps 1-3
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Figure 13-14, Steps 4-5
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Synaptic Transmission
• Nerve cells communicate with one another and
other cell types at synapses
• Electrical synapse: one neuron (presynaptic)
is connected to a second neuron (postsynaptic)
via gap junctions
• Ions move through the junctions between the
cells and there is no delay in transmission
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Figure 13-15
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Figure 13-15A
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Figure 13-15B
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Chemical synapses
• Chemical synapse: presynaptic and
postsynaptic neurons are not connected by gap
junctions
• Instead the two cell membranes are separated
by a small space, the synaptic cleft
• A signal at the terminus of the presynaptic
neuron must be sent to the postsynaptic neuron
chemically
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Figure 13-16
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Figure 13-16A
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Figure 13-16B
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Figure 13-16C
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Neurotransmitters
• Neurotransmitters are stored in synaptic boutons
in the presynaptic neuron, released by the arrival
of an action potential
• They diffuse across the cleft and bind to receptors
in the plasma membrane of the postsynaptic cell
• They are converted into electric signals, to
stimulate or inhibit an action potential in the
receiving cell
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Types of neurotransmitter receptors
• Neurotransmitter receptors fall into two classes
– Ligand-gated ion channels (ionotropic receptors)
– Receptors that exert their effects indirectly via a
system of messengers (metabotropic receptors)
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Figure 13-17
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Figure 13-17A
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Figure 13-17B
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Neurotransmitters Relay Signals
Across Nerve Synapses
• Neurotransmitter: any signaling molecule
released by a neuron, detected by the
postsynaptic cell through a receptor
• Excitatory receptors: cause depolarization of the
postsynaptic neuron
• Inhibitory receptors: cause the postsynaptic cell
to hyperpolarize
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Criteria for neurotransmitters
• To qualify as a neurotransmitter a molecule
must
- 1. Elicit the appropriate response when
introduced to the synaptic cleft
- 2. Occur naturally in the presynaptic neuron
- 3. Be released at the right time when the
presynaptic neuron is stimulated
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Table 13-2
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Acetylcholine
• Acetylcholine is the most common
neurotransmitter in vertebrates in synapses
outside the CNS and for neuromuscular junctions
• It is an excitatory neurotransmitter
• Synapses using acetylcholine as their
neurotransmitter are called cholinergic
synapses
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Catecholamines
• Catecholamines include dopamine and the
hormones norepinephrine and epinephrine
• All are derivatives of tyrosine, and are also
synthesized in the adrenal gland
• Synapses (in the brain and between nerves and
smooth muscles in internal organs) that use
catecholamines as neurotransmitters are called
adrenergic
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Amino Acids and Derivatives
• Some other neurotransmitters consist of amino
acids and their derivatives: histamine, serotonin,
g-amino butyric acid (GABA) as well as glycine
and glutamate
• Serotonin is excitatory (causes potassium
channels to close) and functions in the CNS
• GABA and glycine are inhibitory; glutamate is
excitatory
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Neuropeptides
• Neuropeptides are short amino acid chains
formed by proteolysis of precursor proteins
• Hundreds are known; they act on groups of
neurons and have long-lasting effects
• E.g., enkephalins inhibit the activity of neurons in
the brain that are involved in pain perception
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Elevated Calcium Levels Stimulate
Secretion of Neurotransmitters from
Presynaptic Neurons
• Neurotransmitter secretion is directly controlled
by calcium ion concentration in synaptic boutons
• When an action potential arrives, depolarization
causes a temporary increase in Ca2+ due to
opening of voltage-gated calcium channels
• The neurotransmitters are stored in small
neurosecretory vesicles in the bouton
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Figure 13-18
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Neurotransmitter release
• The release of calcium into the bouton has two
effects
- 1. Vesicles in storage are mobilized for rapid
release
- 2. Vesicles near the membrane that are poised for
release fuse with the plasma membrane and expel
the contents into the cleft
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Video: How synapses work
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Secretion of Neurotransmitters
Involves the Docking and Fusion of
Vesicles with the Plasma Membrane
• Vesicle fusion is thought to involve vesicles that are
already “docked” at the plasma membrane
• Docking and fusion are mediated by t- and
v-SNARE proteins
• Ca2+ in the boutons is bound by synaptogamin,
which undergoes conformational change and
promotes t- and v-SNARES to interact efficiently
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The active zone
• Docking takes place at the active zone where
the synaptic vesicles and calcium channels are
very close together
• Neurotoxins such as tetanus and botulism
interfere with docking and release
• Compensatory endocytosis maintains the size of
the nerve terminal by recycling membranes
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Figure 13-19
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Figure 13-19A
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Figure 13-19B
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Kiss-and-run exocytosis
• When neurons need to fire very rapidly they
use a more transient method for
neurotransmitter release
• A vesicle will temporarily fuse with the plasma
membrane, release some neurotransmitter,
and then reseal
• This is called kiss-and-run exocytosis
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Neurotransmitters Are Detected by
Specific Receptors on Postsynaptic
Neurons
• Each neurotransmitter has a particular
receptor that detects and binds it
• A few of these receptors are quite well
understood
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The Nicotinic Acetylcholine Receptor
• Acetylcholine binds a ligand-gated Na+ channel
called the nicotinic acetylcholine receptor (nAchR)
• When two molecules of acetylcholine bind, the
receptor opens and lets Na+ rush into the cell,
causing depolarization
• nAchR has been studied using the electric organ
of the electric ray (Torpedo californica)
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NAchR structure
• The receptor forms rosette-like particles about
8 nm across
• It consists of four kinds of subunits (, b, g, d)
• The receptors play an important role in
transmitting nerve impulses to muscle; in
humans, autoimmune reactions against these
receptors cause serious illnesses
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Figure 13-20
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Figure 13-20A
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Figure 13-20B
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Figure 13-20C
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Video: The acetycholine receptor
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The GABA Receptor
• The GABA receptor is also a ligand-gated
channel, but when opened, it allows Cl– ions
into the cell
• This causes hyperpolarization of the receiving
cell and decreased likelihood that an action
potential will be generated
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Neurotransmitters Must Be Inactivated
Shortly After Their Release
• Once the neurotransmitter has been secreted, it
must be rapidly removed from the synaptic cleft
• Acetylcholinesterase hydrolyzes acetylcholine
• Neurotransmitter reuptake involves pumping
neurotransmitters back into the presynaptic cell
or nearby support cells
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Integration and Processing of
Nerve Signals
• A single action potential is usually not enough to
cause firing of a postsynaptic cell
• Incremental changes in potential due to
neurotransmitter binding are called postsynaptic
potentials (PSPs)
• These can cause excitatory or inhibitory
postsynaptic potentials depending on the
neurotransmitter
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Neurons Can Integrate Signals from Other
Neurons Through Both Temporal and
Spatial Summation
• Individual action potentials will produce only a
temporary EPSP
• Two action potentials in rapid succession will
result in a more depolarized receiving cell
• A rapid series of action potentials sums EPSPs
over time, and pushes the postsynaptic cell past
its threshold (temporal summation)
© 2012 Pearson Education, Inc.
Spatial summation
• Action potentials received at a single synapse
are usually not sufficient to induce an action
potential
• When many action potentials cause
neurotransmitter release simultaneously, it is
more likely that an action potential will be
induced
•
This is called spatial summation
© 2012 Pearson Education, Inc.
Neurons Can Integrate Both Excitatory
and Inhibitory Signals from Other
Neurons
• Postsynaptic neurons can receive both inhibitory
and excitatory signals
• Neurons can receive thousands of inputs from
other neurons, and physically sum EPSPs and
IPSPs
© 2012 Pearson Education, Inc.
Figure 13-21
© 2012 Pearson Education, Inc.
Figure 13-21A
© 2012 Pearson Education, Inc.
Figure 13-21B
© 2012 Pearson Education, Inc.