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Lecture

NROC61H3 Lecture Notes - Channelopathy, Oligodendrocyte, Axon Hillock


Department
Neuroscience
Course Code
NROC61H3
Professor
S

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NROB60 Chapter 4
Introduction
The frequency and pattern of action potentials constitute the code used by neurons to transfer information
from one location to another.
Properties of the Action Potential
The Ups and Downs of an Action Potential
o See Fig. 4.1.
o The first part, called the rising phase, is characterized by a rapid depolarization of the membrane.
This change in membrane potential continues until Vm reaches a peak value of about 40 mV
o The apart of the action potential where the inside of the neuron is positively charged with respect to
the outside is called the overshoot.
o The falling phase of the action potential is a rapid repolarization until the membrane is actually more
negative than the resting potential
o The last part of the falling phased is called the undershoot (after-hyperpolarization).
o Finally, there is a gradual restoration of the resting potential
o The action potential lasts about 2 milliseconds (msecs).
The Generation of an Action Potential (all-or-none)
o Consider you stepping on a thumbtack
o The initial chain of events is therefore:
1) The thumbtack enters skin
2) The membrane of the nerve fibers in the skin is stretched
3) Na+ - permeable channels open.
a. Because of the large concentration gradient and the negative charge of the cytosol,
Na+ ions enter the fiber through these channels
b. The entry of Na+ depolarizes the membrane (i.e. the cytosolic surface of the
membrane becomes negative)
c. If this depolarization (generator potential) achieves a critical level, the membrane
will generate an action potential. The critical level of depolarization that must be
crossed in order to trigger an action potential is called threshold.
o The depolarization that causes action potentials arises in different ways in different neurons
The Generation of Multiple Action Potentials
o The rate of action potential generation depends on the magnitude of the continuous depolarizing
current
o The firing frequency of action potentials reflects the magnitude of the depolarizing current
This is one way that stimulation intensity is encoded in the nervous system
o There is a limit to the rate at which a neuron can generate action potentials
The maximum firing frequency is about 1000 Hz
Once an action potential is initiated, it is impossible to initiate antoehr for about 1 msec.
This period is called the absolute refractory period.
It can be relatively difficult to initiate another action potential for several milliseconds after the
end of the absolute refractory period
During the relative refractory period, the amount of current required to depolarize
the neuron to action potential threshold is elevated above normal
The Action Potential, In Theory
Depolarization of the cell during the action potential is caused by the influx of sodium ions across the
membrane, and repolarization is caused by the efflux of potassium ions.
Membrane Currents and Conductances
o See Fig. 4.4.
o The membrane of this cell has three types of protein molecules: sodium-potassium pumps, potassium
channels and sodium channels.
o Begin by assuming that both the potassium channels and the sodium channels are closed and that
the membrane potential, Vm, is equal to 0 mV.
Opening the potassium channels only causes the potassium ions to flow out of the cell, down
their concentration gradient, until the inside becomes negatively charged and Vm = Ek.
This movement raises three points:
1) The net movement of potassium ions across the membrane is an electrical current
2) The number of open potassium channels is proportional to an electrical
conductance
3) Membrane potassium current, IK, will flow only as long as Vm ≠ EK. The driving
force on K+ is defined as the difference between the real membrane potential and
the equilibrium potential, and it can be written as VM - EK.
The Ins and Outs of an Action Potential
o What’s happening with the Na+ ions concentrated outside the cell?
The membrane potential is so negative with respect to the sodium equilibrium potential and
there is a driving force on Na+
However there can be no net movement of sodium ions as long as the membrane is
impermeable to Na+
o When the channels are open, however,:
The ionic permeability of the membrane, gNa is high and there is a large driving force pushing
on Na+.
Assuming that the membrane permeability is now far greater to sodium than it is to potassium,
this influx of Na+ depolarizes the neuron until Vm approaches ENa, 62 mV.
o How could we account for the falling phase of the action potential?
Simply assume that sodium channels quickly close and the potassium channels remain open,
so the dominant membrane ion permeability switches back from Na+ to K+. The potassium
ions would flow out of the cell until the membrane potential again equals EK.
The Action Potential, In Reality
When the membrane is depolarized to threshold, there is a transient increase in gNa. The increase in gNa
allows the entry of Na+ ions, which depolarizes the neuron.
Restoring the negative membrane potential would be further aided by a transient increase in gK during the
falling phase, allowing K+ ions to leave the depolarized neuron faster.
The Voltage-Gated Sodium Channel
o Sodium Channel Structure
The voltage-gated sodium channel is created from a single long polypeptide
It has four distinct domains (I-IV) each consisting of six transmembrane alpha helices
(S1 S6).
The pore is closed at the negative resting membrane potential.
When the membrane is depolarized to threshold, the molecule twists into a configuration that
allows the pass of Na+ through the pore.
The sodium channel is 12 times more permeable to Na+ than to K+.
The sodium channel is gated by a change in voltage across the membrane
o Functional Properties of the Sodium Channel
Changing the membrane potential from -65 to -40 mV causes these channels to pop open
See Fig. 4.9.
These voltage-gated sodium channels have a characteristic pattern of behaviour:
1) They open with little delay
2) They stay open for about 1 msec and then close (inactivate)
3) They cannot be opened again by depolarization until the membrane potential
returns to a negative value near threshold
The fact that single channels do not open until a critical level of membrane
depolarization is reached explains the action potential threshold.
The rapid opening of the channels in response to depolarization explains why the
rising phase of the action potential occurs so quickly
The short time the channels stay open before inactivating partly explains why the
action potential is so brief.
Inactivation of the channels can account for the absolute refractory period
Single amino acid mutations in the extracellular regions of one sodium channel have been
shown to cause a common inherited disorder in human infants known as generalized epilepsy
with febrile seizures.
Generalized epilepsy with febrile seizures is a channelopathy, a human genetic disease
caused by alterations in the structure and function of ion channels.
o The Effects of Toxins on the Sodium Channel
Tetrodotoxin (TTX) clogs the Na+ - permeable pore by binding tightly to a specific site on the
outside of the channel.
TTX blocks all sodium-dependent action potentials
Voltage-Gated Potassium Channels
o There are many different types of voltage-gated potassium channels.
o Most of them open when the membrane is depolarized and function to diminish any further
depolarization by giving K+ ions a path to leave the cell across the membrane
o The channel proteins consist of four separate polypeptide subunits that come together to form a pore
between them
These proteins are sensitive to changes in the electrical field across the membrane
o When the membrane is depolarized, the subunits are believed to twist into shape that allows K+ ions
to pass through the pore.
Putting the Pieces Together
o The key properties of the action potential can be explained using these terms:
Threshold: membrane potential at which enough voltage-gated sodium channels open so that
the relative ionic permeability of the membrane favours sodium over potassium
Rising Phase: When the inside of the membrane has a negative electrical potential, three is a
large driving force on Na+ ions. Therefore, Na+ ions rush into the cell through the open sodium
channels, causing the membrane to rapidly depolarize.
Overshoot: because the relative permeability of the membrane greatly favours sodium, the
membrane potential goes to a value close to ENa, which is greater than 0 mV.
Falling phase: the behaviour of two types of channel contributors to the falling phase. First, the
voltage gated sodium channels inactivate. Second, the voltage-gated potassium channels
finally open. There is a great driving force on K+ ions rush out of the cell through the open
channels, causing the membrane potential to become negative again.
Undershoot: the open voltage-gated potassium channels add ot the resting potassium
membrane permeability. Because there is very little sodium permeability, the membrane
potential goes toward EK, causing a hyperpolarization relative to the resting membrane
potential until the voltage-gated potassium channels close again.
Absolute refractory period: sodium channels inactivate when the membrane becomes strongly
depolarized. They cannot be activated again, and another action potential cannot be
generated, until the membrane potential goes sufficiently negative to deactivate the channels.
Relative Refractory Period: The membrane potential stays hyperpolarized until the voltage-
gated potassium channels close. More depolarizing current is required to bring the membrane
potential to threshold.
Action Potential Conduction
When the axon is depolarized sufficiently to reach threshold, voltage-gated sodium channels open, and the
action potential is initiated.
o The influx of positive charge depolarizes the segment of membrane immediately before it until it
reaches threshold and generates its own action potential
An action potential initiated at one end of an axon propagates only in one direction; it does not turn back on
itself. This is because the membrane just behind it is refractory, due to inactivation of the sodium channels
o An action potential can be generated by depolarization at either end of the axon and therefore can
propagate in either direction.