BCHE4040/LSCI5440-Aspects of

Neuroscience

Section 6: Ion channels, action

potentials and signal conduction
(Part 1)

Kim Hei-Man CHOW, PhD

Assistant Professor
Room 604, Mong Man Wai Building
Biochemistry Program
School of Life Sciences
Email: heimanchow@cuhk.edu.hk
Key learning objectives (Section 6)
1. The need for faster communication
2. Roles of different cells in an action potential
3. Ion channels and ion transporters
4. 5 stages of an action potential
5. Unique properties of voltage-gated Na+ channels
6. Axon hillock
7. Postsynaptic potentials
8. Receptor potentials
9. Toxins that screw up our nervous system
 Information transmission and processing
• Simple, single cells like bacteria
• Chemical gradients
• Food – swim up the gradient Signals Response

• Nasty stuff – swim down the gradient

• Quorum sensing
• Physical gradients
• Temperature, viscosity, etc.

• Multicellular organisms require coordination

• Chemical coordination (hormones) like chemicalSignals
gradients in bacteria
• Slow and not accurate
Response
 Speed matters!
Electrical mechanisms much better
They move information at high speed!
Allow rapid responses
• Escape
• Attack prey
• Mate

How fast is fast by definition?

 Cells that matter in action potential
Astrocytes take up
Neurons—where metabolites from the
action potential blood and provide
actually occurs metabolic support to
the cell body and
dendrites of neurons
Endothelial cells supply
nutrients from the
blood circulatory
system
Oligodendrocytes—
myelinate axons of
neurons for speeding
up an action potential,
provide metabolic
support to axonal
region of a neuron

Action potential is extremely energy demanding, therefore adequate fuel metabolic support to neurons is needed
Neurons—Where electricity is fired!
INPUT system = analogous to the
dendrites, which each of which receives
chemical signals from other neurons, which
are then converted into electrical impulses
that are transmitted to the cell body

PROCESSOR =cell body of a neuron that

receives and integrate information
collected by dendrites and other synaptic
inputs in determining the messages shall be
transmitted to other cells or not through its
axon

OUTPUT system = analogous to the axon of

the neuron, which if propagates the
information/signal to the input of the next
machinery (neuron), through a synapse
 Electric current is a flow of ions
Electric current definition: the amount of electric
charges past a specified circuit point per unit time and
it is expressed in amperes (A)

In cell physiology, the flow of ions occurs at the cell

membrane, through ion channels and pumps, often
as part of depolarization or repolarization events
happening during the action potential in neurons.
 Ion channels versus Ion transporters (pumps)
Ion transporters
1. Transporters/pumps are
Ion channels transmembrane proteins
1. Pore-forming membrane that transport ions across
proteins allow movement of the cell membrane against
ions through the cell the concentration gradient.
membrane 2. Ion transports follows the
2. Ion transportation follows low-to-high against the
the electrochemical gradient electrochemical gradient
3. Passive transport 3. Active transport, requires
4. Example: voltage-gated ion utilization of ATP
channels, ligand-gated ion 4. Example: ABC transporters
channels (ATP binding and cassette
transporters)
Electrochemical gradient
Concentration gradient is important for
movement of molecules; but voltage difference
between the two sides of the membrane can also
play a role

When molecules are non-charged:

The movement would be based on concentration
gradient ONLY, voltage difference plays no role.

When molecules are charged:

1. The movement would be based on the
combined force due to membrane voltage
gradient and concentration gradient
2. When both the concentration and voltage
gradient work together in the same
directionà larger electrochemical gradient
3. When the concentration and voltage gradient
work in the opposite directionà small
electrochemical gradient
 Ion channels in neuronal plasma membrane

1. Non-gated resting channels (a.k.a. leaky channels):

Always open, leaky (K+ channels)
2. Gated channels:
A. Voltage-gated: open transiently in response to change in voltage—participate in the propagation of action
potentials
B. Ligand-gated: open or close in response to particular chemical stimuli (hormones, neurotransmitters)
C. Mechanically-gated: open when physical stimuli such as stretching forces act on the membrane of the
channel
D. Signal-gated: open in response to an intracellular signaling molecules, e.g. cAMP
Major ion channels for CNS neuronal action potential

Voltage-gated ion channels Ligand-gated ion channels at the post

long the axon (see next slide) synaptic region of a neuron (dendrites):
1. Glutamatergic receptors
2. GABAergic receptors
 Major types of Voltage-gated ion channels
1. Voltage-gated Na+ channels
• Regulate the depolarization during action potentials
2. Voltage-gated K+ channels Extracellular

• Regulate the repolarization during action potentials, and restore

the resting membrane potential
3. Voltage-gated Ca2+ channels
• At the presynaptic terminal, they regulate secretion of Cytosol
neurohormones and release of neurotransmitters (recall the
neurotransmitter recycling slide, this induces the trigger for vesicle Extracellular
fusion)
• At the postsynaptic terminal, they regulate neuronal excitability and
long-term potentiation.
4. Voltage-gated Cl- channels
• Participate in regulating excitability and assists in restoring the
resting membrane potential after the action potential
Cytosol
The difference in ion concentration across cell membrane at rest
Cytosol Extracellular space

1. Differences across the membrane are maintained by various ion pumps

2. The flow direction of the ions through these voltage-gated ion channels (passive) follows
the electrochemical gradient.
3. X- represents proteins, which in general have a negative charge at the neutral pH
 Before firing: Stage 0-Resting membrane potential
1. A neuron at rest is said to be negatively
charged: the inside of a cell is
approximately 70 millivolts (resting
potential) more negative than outside.
2. Caused by difference in concentrations of
K+ and Na+ ions inside and outside of the
cell
3. Negative charge is created by the cell
membrane being more permeable to K+
ion movement than sodium ion
movement.
4. In resting neurons: K+ is high inside/Na+ is high outside the cells. This is due to
• active pumping of Na+/K+ pumps(2K+ comes in/3 Na+ goes out)
• neurons processes both K+ and Na+ leakage channels that allow two cations to diffuse down their
gradient, however neurons have far more leaky K+ channels than Na+ channels, meaning the resting
cell membrane is more permeable to potassium than to sodium
5. More K+ goes out, less Na+ comes in à slightly negative inside relatively
6. The cell's resting potential is roughly -70 mV.
 Overview—Generation of an action potential
1. Transmission of a signal between neurons is generally
carried by a chemical called a neurotransmitter.
2. Transmission of a signal within a neuron (from dendrite
to axon terminal) is carried by a brief reversal of the
resting membrane potential called an action potential.
3. An action potential is a sudden, transient depolarization
of the axonal membrane followed by repolarization to
the resting potential at about -70mV
4. Mediated by voltage-gated ion channels

Terminology:
1. -70mV = resting potential
2. -70mV<X<-55mV = Passive potential, failed initiations
3. -55mV = threshold for an action potential
4. Depolarization = getting more positive (inside)
5. Repolarization = getting more negative (inside)
6. Hyperpolarization = value more negative than -70mV
7. Stimulus: from excitatory neurotransmitter, e.g.
glutamate
 Stage 1—Action potential: depolarization
1. Upon receiving excitatory signals, this
stimulus induces opening of voltage-gated
Na channels, allowing Na+ ions to rush in,
results in depolarization of the membrane.
2. Depolarization—decrease the difference in
voltage between inside and outside of a
neuron.

3. Sufficient stimulus depolarize the target neuron to its threshold potential (-

55mV), this induces voltage-gated Na+ channels at the axon hillock to
open, allowing positive ions to enter the cell.
4. Once these Na+ channels open, the neuron completely depolarizes to
membrane potential to about +30-40mM, by reaching this voltage, the Na+
channels closes
5. Action potentials are considered as “all-or-nothing” events. That means,
once threshold is reached, the neuron always completely depolarizes.
 Stage 2—Action potential: repolarization
1. Once depolarization is complete, the cell
must now reset its membrane voltage back
to the resting potential.
2. At +40mV, voltage-gated Na+ channel is
“inactive”, while voltage-gated K+ channels
now open
3. As K+ is high inside the cells, K+ rushes out
the cells by concentration gradient and
electrostatic pressure (as very +ve inside),
thereby reducing the positive charge inside
the cell, i.e. repolarization.
4. K+ channels started shutting down once
membrane potential reached -70mV, the
time lag causes an overshoot of K+ out of the
cell, i.e. hyperpolarization

Hyperpolarization
 Stage 3—Action potential: Hyperpolarization
The extra efflux of potassium ions from the
neuron results in a brief (approximately 1
millisecond) period of Hyperpolarization

A phase where some potassium channels

remain open and sodium channels remain
inactivated (shut but cannot be activated
versus the original ”close” stage)

In this particular axonal region when

membrane potential is hyperpolarized:
1. Another action potential cannot be
triggered
2. Ensuring the action potential travels
towards one direction X
Hyperpolarized X<-70mM ~-70mV
“no go” “go”
 Stage 4—Action potential: late refractory period
At this time, this axonal region faces two challenges:
1. Membrane potential more negative than resting -70mV
2. K+ high outside, Na+ high inside (Reminder at resting potential: K+ is high
inside/Na+ is high outside)
At this stage, all voltage-gated ion channels closes (voltage-gated Na+ channel still
inactiveànot responsive):
1. The leaky K+ channels now comes at play. As neurons process far more K+ channels
than Na+ channels and that they always open, K+ leaks in along its electrochemical
gradient
2. To further facilitate the removal of intracellular Na+ and brings more K+ in, The *
Na+/K+ ATPase pump (3Na+ out/2 K+ in) [electrochemically, this also help more K+
comes in from the leaky channels)
3. Eventually, the cell goes back to -70mV, at resting stage
Na+/K+ ATPase pump
1. Responsible for the usage of 30% of body’s ATP (explains why neurons are energy
demanding)
2. 1 ATP is hydrolyzed for pumping 3 Na+ out and 2 K+ in
3. Eventually the ion gradient can be reversed back to resting state (i.e. K+ is high
inside/Na+ is high outside)
 Unique properties of voltage-gated Na+ channels
What leads to reactivation
(return back to the closed
stage from the inactivated
stage)???

Ans: Time !!!!!!

3 States:
1. Closed—The only state which is responsive to stimulation
2. Open—It’s already opened, so it is under stimulation
3. Inactivated—This state looks similar to “close”, but it is not responsive to stimulation,
occurs after 0.5-1ms upon opening (reaching +40mV), it automatically closes by the
inactivation gate. It has to be reset to “close” in order to becoming responsive to
stimulation
 Refractory period-Absolute refractory period
Definition: the time period which the axonal portion cannot
response to another stimulus

1. Absolute refractory period (Pink region)--Voltage gated Na+

channels are opened upon stimulus reaching the threshold. At 0.5-
1ms after opening, it automatically becomes inactivated. Thus
another action potential cannot be generated in this part of the axon.
Upon voltage starts dropping until reaching hyperpolarization, some
(very few and almost none; as its time-dependent) of these voltage-
gated Na+ channels started to reset to ”closed” state.

Why there isn’t’ any other action potential occurs during repolarization?
1. As voltage-gated Na+ channels are inactivated, it is not responsive to
any stimulus.
2. Absolute refractory periods help direct the action potential down the axon,
because only channels further downstream can open and let in depolarizing
ions.
 Refractory period-Relative refractory period
2. Relative refractory period (Yellow region)—as membrane
repolarizes more and reached the hyperpolarized state, this allows the
re-setting of MORE voltage gated Na+ channels from inactive to closed
state.

Reminder: When membrane potential reaches below -70mM

(hyperpolarization), at this stage, voltage gated K+ channels close.

Why an action potential is possible (relative to absolute refractory

period) but is still much harder than normal (at rest) to occur during
relative refractory period?
1. This is the period after the absolute refractory period, when the
Na+ gated ion channels started to reset. à becoming responsive
to stimulus (explains why it is possible)
2. However, the cell is still hyperpolarized after sending an action
potential. It would take even more positive ions than usual to
reach the appropriate depolarization potential than
usual. (explains why it is harder than at rest)
 Concept check (T/F)—After the second part
1. Ion pumps are involved in the rapid depolarization of a neuron during an action potential
2. Voltage-gated K+ channel have 3 configurations
3. If the membrane potential is above threshold, the neuron is said to be polarized
4. A neuron is very energy demanding due to activities of the voltage-gated Na+ channel
5. Although the action potential occurs at the axonal region of neurons, glial cells are also important in
needed to provide supports
6. Axon hillock is the initiation point of depolarization
7. Axon hillock belongs to the cell body of the neuron
8. Depolarization begins at dendrites
9. Postsynaptic potentials involves voltage-gated ion channels
10. Postsynaptic potentials involves the transformation of chemical signals to electrical signals
11. GABA induces EPSC while glutamate induces IPSC
12. At dendrites, potentials are graded while in axon, potentials are all-or-none
13. Potentials at dendrites have refractory periods
14. The amplitude of action potentials can be summed up
15. Tetrodotoxin is toxic by irreversibility opens sodium channels
Further Reading