1. The contestants died from pufferfish poisoning which works by maintaining sodium channels in an open state. This prevents repolarization and causes paralysis. 2. Saltatory conduction allows faster propagation of action potentials along myelinated axons. The myelin sheath insulates between nodes of Ranvier, allowing the signal to jump from node to node. 3. An action potential is initiated when a stimulus is strong enough to depolarize the membrane past threshold. Following an action potential is an absolute refractory period where sodium channels are inactivated and a relative refractory period where some channels recover.

1. Membrane potentials
Dr G Bhanu Prakash

2. Objectives
To understand the shape and form of the
action potential and understand how it
arises in terms of the changes in the
underlying Na+ and K+ channels
To explore how action potentials are
conducted in axons and how this is
affected by myelin

3. Electrocardiogram
ECG

4. Electroencephalogram
EEG

5. Electromyogram
EMG

6. Extracellular Recording

7. Intracellular Recording

8. Opposite charges attract each other and
will move toward each other if not separated
by some barrier.

9. Only a very thin shell of charge difference
is needed to establish a membrane potential.

11. Resting membrane potential
（静息电位）
A potential difference across
the membranes of inactive
cells, with the inside of the cell
negative relative to the outside
of the cell
Ranging from –10 to –100 mV

12. Depolarization
occurs
when ion
movement
reduces the
charge
imbalance.
A cell is
“polarized”
because
its interior
is more
negative
than its
exterior.
Overshoot refers to
the development of
a charge reversal.
Repolarization is
movement back
toward the
resting potential.
Hyperpolarization is
the development of
even more negative
charge inside the cell.
（极化）
（去极化） （超极化）
（复极化）
（超射）

13. chemical
driving force
electrical
driving force
++++++++++++++++
- - - - - - - - - - - - - - - - -
electrochemical
balance

14. The Nernst Equation:
K+
equilibrium potential (EK) (37o
C)
i
o
Ion
Ion
ZF
RT
E
][
][
log=
R=Gas constant
T=Temperature
Z=Valence
F=Faraday’s constant
)(
][
][
log60 mV
K
K
Ek
i
o
+
+
=

15. Begin:
K+
in Compartment 2,
Na+
in Compartment 1;
BUT only K+
can move.
Ion movement:
K+
crosses into
Compartment 1;
Na+
stays in
Compartment 1.
buildup of positive charge
in Compartment 1 produces an electrical potential that
exactly offsets the K+
chemical concentration gradient.
At the potassium
equilibrium potential:

16. Begin:
K+
in Compartment 2,
Na+
in Compartment 1;
BUT only Na+
can move.
Ion movement:
Na+
crosses into
Compartment 2;
but K+
stays in
Compartment 2.
buildup of positive charge in Compartment 2
produces an electrical potential that exactly
offsets the Na+
chemical concentration gradient.
At the sodium
equilibrium potential:

17. Mammalian skeletal muscle cell -95 mV -90 mV
Frog skeletal muscle cell -105 mV -90 mV
Squid giant axon -96 mV -70 mV
Ek Observed RP
Difference between EK and directly measured
resting potential

18. Goldman-Hodgkin-Katz equation

19. •Electrogenic
•Hyperpolarizing
Role of Na+
-K+
pump:
Establishment of resting
membrane potential:
Na+/K+ pump establishes
concentration gradient
generating a small
negative potential; pump
uses up to 40% of the
ATP produced by that
cell!

20. Origin of the normal resting membrane
potential
K+
diffusion potential
Na+
diffusion
Na+
-K+
pump

22. Action potential
Some of the cells (excitable cells) are capable to rapidly reverse their
resting membrane potential from negative resting values to slightly
positive values. This transient and rapid change in membrane potential
is called an action potential

23. Negative after-
potential
Positive
after-potential
Spike potential After-potential
A typical neuron action potential

24. Electrotonic Potential

25. The size of a
graded potential
(here, graded
depolarizations)
is proportionate
to the intensity
of the stimulus.

26. Graded potentials can be: EXCITATORY or INHIBITORY
(action potential (action potential
is more likely) is less likely)
The size of a graded potential is proportional to the size of the stimulus.
Graded potentials decay as they move over distance.

27. Graded potentials decay as they move over distance.

28. Local response
• Not “all-or-none”
• Electrotonic propagation:
spreading with decrement
• Summation: spatial &
temporal

29. Threshold Potential: level of depolarization needed to trigger
an action potential (most neurons have a threshold at -50 mV)

30. Membrane potentials

31. Objectives
To understand the shape and form of the
action potential and understand how it
arises in terms of the changes in the
underlying Na+ and K+ channels
To explore how action potentials are
conducted in axons and how this is
affected by myelin

32. Review
Intracellular and extracellular recording
Resting membrane potential (definition
and mechanism)
Action potential (definition)
Local response (Graded potential)
Threshold potential

33. Ionic basis of action potential

34. Voltage Clamp
Nobel Prize in Physiology or
Medicine 1963
"for their discoveries concerning the ionic
mechanisms involved in excitation and
inhibition in the peripheral and central
portions of the nerve cell membrane"
Eccles Hodgkin Huxley

35. Patch Clamp
Nobel Prize in Physiology or
Medicine 1991
"for their discoveries concerning the
function of single ion channels in cells"
Erwin Neher Bert Sakmann

36. Figure 2 Instantaneous I–V data reveal that IK has a more hyperpolarised reversal potential than IA
A, tail current family for IK, recorded in 5 mM 4-AP. Following a 100 ms step to +53 mV, the membrane potential
was stepped to a level ranging from +53 to -117 mV in 10 mV increments. Each trace is an average of 12
interleaved episodes. Leak currents have been subtracted. B, plot of peak instantaneous IK, from extrapolated
exponential fits to the tail currents (Methods), versus tail potential for this patch. The superimposed curve is a
quadratic polynomial. The reversal potential for this patch was -86.4 mV. C, tail current family for IA, recorded in
30 mM TEA and shown expanded in the inset. The pulse protocol was as in A, except the duration of the
prepulse to +53 mV was 1.5 ms. Each trace is an average of 6 interleaved episodes. Leak currents have been
subtracted. The slowly rising trace in the inset is the estimated time course of the contaminating IK at +53 mV in
this patch. At 1.5 ms the contamination is about 10 % of IA. D, plot of peak instantaneous IAversus tail potential
for this patch. The fitted quadratic polynomial gives a reversal potential of -68.7 mV.
From:
doi:
10.1111/j.1469-7793.2000.t01-1-00593.x
June 15, 2000 The Journal of Physiology, 525, 593-
609

37. (1) Depolarization:
Activation of Na+
channel
Blocker:
Tetrodotoxin (TTX)
(2) Repolarization:
Inactivation of Na+
channel
Activation of K+
channel
Blocker:
Tetraethylammonium
(TEA)

39. The rapid opening of voltage-gated Na+
channels
explains the rapid-depolarization phase at the
beginning of the action potential.
The slower opening of voltage-gated K+
channels
explains the repolarization and after hyperpolarization
phases that complete the action potential.

42. An action potential
is an “all-or-none”
sequence of changes
in membrane potential.
Action potentials result
from an all-or-none
sequence of changes
in ion permeability
due to the operation
of voltage-gated
Na+
and K +
channels.
The rapid opening of
voltage-gated Na+
channels
allows rapid entry of Na+
,
moving membrane potential
closer to the sodium
equilibrium potential (+60 mv)
The slower opening of
voltage-gated K+
channels
allows K+
exit,
moving membrane potential
closer to the potassium
equilibrium potential (-90 mv)

43. Mechanism of the
initiation and
termination of AP

44. How to re-establish Na+
and K+
gradients after action potential ?
Concentration gradient of Na+
and K+
Extracellular (mmol/L) Intracellular (mmol/L)
Na+
150.0 15.0
K+
5.0 150.0

47. For a television game show, 16 contestants volunteer to be stranded on
a deserted island in the middle of the South China Sea. They must rely
on their own survival instincts and skills. During one of the challenges,
one team wins a fishing spear. They catch a puffer fish and cook it over
the open flames of their barbecue. None of them are very skilled in
cooking, but they enjoy the fish anyway. One of the contestants, a
worldwide traveler, comments that it tastes like Fugu. After dinner, they
all develop a strange tingling around their lips and tongue. They all
become weak, and their frailty progresses to paralysis. They all die.
What is the mechanism of toxicity?
 A Blockage of the sodium gates
 B Blockage of the potassium gates
 C Interference with the release of acetylcholine
 D Antibody directed against the acetylcholine receptor
 E Maintaining the sodium channel in an open state

48. For a television game show, 16 contestants volunteer to be stranded on
a deserted island in the middle of the South China Sea. They must rely
on their own survival instincts and skills. During one of the challenges,
one team wins a fishing spear. They catch a puffer fish and cook it over
the open flames of their barbecue. None of them are very skilled in
cooking, but they enjoy the fish anyway. One of the contestants, a
worldwide traveler, comments that it tastes like Fugu. After dinner, they
all develop a strange tingling around their lips and tongue. They all
become weak, and their frailty progresses to paralysis. They all die.
What is the mechanism of toxicity?
 A Blockage of the sodium gates
 B Blockage of the potassium gates
 C Interference with the release of acetylcholine
 D Antibody directed against the acetylcholine receptor
 E Maintaining the sodium channel in an open state

49. Conduction of action potential
Continuous propagation
in the unmyelinated axon

50. Saltatory propagation in
the myelinated axon
http://www.brainviews.com/abFiles/AniSalt.htm

51. Saltatorial Conduction: Action potentials jump from one node to the
next as they propagate along a myelinated axon.

52. Excitation and Excitability
To initiate excitation (AP)
 Excitable cells
 Stimulation
 Intensity
 Duration
 dV/dt

53. Strength-duration Curve

54. Four action potentials,
each the result of a
stimulus strong enough to
cause depolarization, are
shown in the right half of
the figure.
Threshold intensity&
Threshold stimulus

55. Refractory period following an AP:
1. Absolute Refractory Period: inactivation of Na+
channel
2. Relative Refractory Period: some Na+
channels open

57. The propagation of the action potential from the dendritic
to the axon-terminal end is typically one-way because the
absolute refractory period follows along in the “wake”
of the moving action potential.

58. Factors affecting excitability
Resting potential
Threshold
Channel state

59. A well-meaning third year medical student accidentally pushes an
unknown quantity of KCl IV to a patient. If the concentration of
potassium outside a neuron were to increase from 4 mEq/L to 8
mEq/L, what would you expect to happen to the minimal stimulus
required for initiation of an action potential?
 A The minimal stimulus required for initiation of an action potential would remain
the same
 B The minimal stimulus required for initiation of an action potential would increase
 C The minimal stimulus required for initiation of an action potential would decrease
 D The minimal stimulus required for initiation of an action potential would stay the
same, but the amplitude of the peak of the action potential would increase
 E The minimal stimulus required for initiation of an action potential would stay the
same, but the conduction velocity of the action potential down an axon would slow

60. A well-meaning third year medical student accidentally pushes an
unknown quantity of KCl IV to a patient. If the concentration of
potassium outside a neuron were to increase from 4 mEq/L to 8
mEq/L, what would you expect to happen to the minimal stimulus
required for initiation of an action potential?
 A The minimal stimulus required for initiation of an action potential would remain
the same
 B The minimal stimulus required for initiation of an action potential would increase
 C The minimal stimulus required for initiation of an action potential would decrease
 D The minimal stimulus required for initiation of an action potential would stay the
same, but the amplitude of the peak of the action potential would increase
 E The minimal stimulus required for initiation of an action potential would stay the
same, but the conduction velocity of the action potential down an axon would slow

61. Sydney Ringer published 4 papers in the
Journal of Physiology in 1882 and 1883,
while working as a physician in London.
Sydney Ringer and his work on ionic composition of buffers
He found that
133mM NaCl,
1.34mM KCl,
2.76mM NaHCO3
1.25mM CaCl2
could sustain the frog heart beat.
J Physiol 2004, 555.3; 585-587
Biochem J 1911, 5 (6-7).
1835-1910
He wrote “The striking contrast between
potassium and sodium with respect to this
modification (wrt refractoriness) is of great
interest….because, from the chemical point
of view, it would be quite unlooked for in two
elements apparently so akin”
Ringer found that in excess potassium the
period of diminished excitability is
increased, and frequnecy of heart beats
diminishes.

62. A rather somber application note: Death by lethal injection
Lethal injection is used for capital punishment in some states with the death penalty.
Lethal injection consists of (1) Sodium thiopental (makes person unconscious), (2)
Pancuronium/tubocurare (stops muscle movement), (3) Potassium chloride
(causes cardiac arrest).
It seems a bit sick, but we can understand how this works from what we know about
electrical signalling. Recall that
iNaiK
oNaoK
NaPKP
NaPKP
mVVm
][][
][][
log54.61 10
+
+
=
ii
oo
mVVm
]15[1]100[40
]150[1]5[40
log54.61 10
+
+
=
mVmVVm 65
4015
350
log54.61 10
−==
ii
oo
mVVm
]15[1]100[40
]150[1]95[40
log54.61 10
+
+
=
mVmVVm 4.0
4015
3950
log54.61 10
−==
This explains what Sydney Ringer
observed in frog hearts in 1882!

63. SUMMARY
Resting potential:
 K+
diffusion potential
 Na+
diffusion
 Na+
-K+
pump
Graded potential
 Not “all-or-none”
 Electrotonic propagation
 Spatial and temporal summation

64. Action potential
 Depolarization: Activation of voltage-gated
Na+ channel
 Repolarization: Inactivation of Na+ channel,
and activation of K+ channel
Refractory period
 Absolute refractory period
 Relative refractory period

65. THANK YOU!