1) The document discusses the electrochemical basis of the action potential in excitable cells such as neurons. It describes how ion gradients across the cell membrane give rise to resting membrane potentials and how threshold stimuli lead to changes in membrane permeability and regenerative depolarization. 2) The work of Hodgkin, Huxley, and others is summarized, showing that the rising phase of the action potential is due to sodium influx and the falling phase to potassium efflux. Their model describes changes in sodium and potassium conductance that underlie action potential generation and propagation. 3) Myelination is described as increasing the speed of action potential propagation along axons by increasing membrane resistance and decreasing capacitance at the nodes of Ran

1. Ionic basis of action potential and its
propagation

2. Resting membrane potential
Oscilloscope display Kandel ER et al. Principles of Neural Science, 5th ed. 2013

3. Resting membrane potential of different
cells
Neuron -70mV
Mammalian skeletal muscle -80mV
Smooth muscle cells -55mV
Cardiac muscle(atrial & ventricular) -80mV
Cardiac purkinje fibres -90mV
AV nodal cell -65mV
Human erythrocyte -9mV
Kandel ER et al. Principles of Neural Science, 5th ed. 2013

4. Various roles of Membrane potential
Kadir LA. Frontiers in Physiology. 2018
Contractility of smooth muscle cells
Electromechanics of the cochlear hair cells
Secretion - pancreatic β cells
Volume control - Chondrocytes, glial cells
Cell cycle & proliferation
Cell migration & wound healing
Pigmentation

5. Distribution of major ions across the
membrane of gaint axon of Squid at rest
Conc in ICF Conc ECF
(mM) (mM)
K+ 400 20
Na+ 50 440
Cl- 52 560
A- 385 none
(organic ions)
Kandel ER et al. Principles of Neural Science, 5th ed. 2013

6. Membrane potential is determined by ion
gradients
Kandel ER et al. Principles of Neural Science, 5th ed. 2013
Ek = -75mV ENa = +55mV

7. Carlo Matteuci (1842)
measured an injury current between the cut and the intact surface of
nerve or muscle
Emil du Bois-Reymond (1848)
showed that this injury current decreased during repetitive
stimulation; the decrease was called the negative variation
Edward Carmeliet. Physiol Rep. 2019

8. Edward Carmeliet. Physiol Rep. 2019
Upon cathodic stimulation the membrane loses its selective permeability to K+ ions and becomes permeable
to all ions: the injury current drops to zero, this is the negative variation
Julius Bernstein
(1868)

9. Kenneth Cole and Howard Curtis (1939)
Edward Carmeliet. Physiol Rep. 2019
During an impulse the conductance of surface membrane increases about 40 fold

10. Hodgkin and Huxley (1945)
Hodgkin A L and Huxley A F J Physiol 1945:176-195

11. What is action potential
A transient, regenerative electrical signal, that propagates,
over a distance, along the cell membrane of excitable cells in
response to an excitation stimulus is called an action potential
Purves et al. Neuroscience 2008,4th ed

12. Action potential
Boron & Boulpaep. Medical Physiology 2017,3rd ed

13. Boron & Boulpaep. Medical Physiology 2017,3rd ed

14. Response to graded current stimuli
Boron & Boulpaep. Medical Physiology 2017,3rd ed

15. Response to stimuli as a function of distance
Boron & Boulpaep. Medical Physiology 2017,3rd ed

16. Refractory period
Boron & Boulpaep. Medical Physiology 2017,3rd ed

17. What is the electrochemical basis of action potential ?
Why do excitable cells exhibit threshold behavior ??
Why do excitable cells have refractory period ???

18. Hodgkin and Huxley (1949)
Hodgkin A L and Huxley A F J Physiol 1945:176-195

19. Hodgkin AL and Katz B J Physiol 1949:37-77
Sodium free solutions
Action of isotonic dextrose

20. Dissection of currents
Hodgkin A L and Huxley A F J Physiol. 1952 a,b,c

21. Changes in Na+ and K+ conductance
Hodgkin A L and Huxley A F J Physiol. 1952 a,b,c

22. Changes in ionic conductance that underlie Action
potential
Boron & Boulpaep. Medical Physiology 2017,3rd ed

23. Refractory period
Inactivation of the Na+ conductance
Increase in K+ conductance
Na+ conductance recover from inactivation
Decrease in K+ conductance

24. The Hodgkin-Huxley model
Hodgkin A L and Huxley A F J Physiol. 1952 a,b,c

25. Na+ ions participate in the depolarization phase
of action potential
Tetraethyl-ammonium : K current blocker
Hille B. J Gen Physiol. 1967

26. K+ ions participate in the repolarization phase of
action potential
Tetrodotoxin: Na current blocker
Hille B. J Gen Physiol. 1967

27. Macroscopic current-voltage relation of the two currents
Boron & Boulpaep. Medical Physiology 2017,3rd ed

29. Kandel ER et al. Principles of Neural Science, 5th ed. 2013

30. Ionic current
Capacitive current
Components of membrane current
Armstrong, C.M. and F. Bezanilla, Nature, 1973

31. Dielectric membrane
+
+
+
+
+
+
+
+
+
+
+ +
+
+
-
-
-
-
-
-
-
-
-
-
-
-
External electrode
Internal electrode
Capacitive current: Linear current
Armstrong, C.M. and F. Bezanilla, Nature, 1973

32. Capacitive current: Nonlinear dielectric
current
+
-
External electrode
Internal electrode
Trapped
charges
Armstrong, C.M. and F. Bezanilla, Nature, 1973

33. How to measure non-linear component?
P/4 method
depolarizing “test” step from -70 mV to +10 mV
Ic(total) = Icl + Icn (non zero)
“control” step from -150mV to -130 mV
Ic(total) = Icl + Icn (zero)
Armstrong, C.M. and F. Bezanilla, Nature, 1973

34. ON current and Sodium ionic current
Armstrong, C.M. and F. Bezanilla, Nature, 1973

35. ON and OFF Sodium gating currents
Armstrong, C.M. and F. Bezanilla, J. Gen. Physiology,

36. Comparison of computed ionic and gating
currents
Gating current (orange
trace)
Sodium current (blue
trace) Francisco Bezanilla. J. Gen. Phy.

37. Armstrong, C.M. and F. Bezanilla, J. Gen. Physiology,
Fast ON and Slow ON
components

38. Gating current at the single-channel level is a jump
process
Francisco Bezanilla, J. Gen. Physiology, 2018

39. The primary structures of the subunits of the
voltage-gated sodium channels
Ahern CA et al. Review. J Gen Physiology.

40. Chanda.B and F. Bezanilla, J. Gen. Physiology,
Four domains of the sodium channel and their
gating
kinetics
Nav1.4 channel

41. Domain-swapped arrangement
Ahern CA et al. Review. J Gen Physiology.

42. Architecture of the NavAb pore
Ahern CA et al. Review. J Gen Physiology.
Aspartate (DI S5–S6 loop)
Glutamate (DII S5–S6 loop)
Lysine (DIII S5–S6 loop)
Alanine (DIV S5–S6 loop)

43. The structure of the voltage sensor
Ahern CA et al. Review. J Gen Physiology.

44. Ahern CA et al. Review. J Gen Physiology.

45. Potassium channels
Delayed outward rectifiers
Transient outward rectifiers
Ca2+ activated K+ currents
Inward rectifiers
Boron & Boulpaep. Medical Physiology 2017,3rd ed

46. Kir K+ channels mediate inward-rectifier K+
currents
Boron & Boulpaep. Medical Physiology 2017,3rd ed

47. Boron & Boulpaep. Medical Physiology 2017,3rd ed

48. Restoration of resting state
• Na+, K+-ATPase pump: Three Na+ ions are extruded for every
two K+ ions transported into the cell
• The Na +K+ pump consists of two subunits
Purves et al. Neuroscience 2008,4th ed

49. Na+K+ pump operate through conformational
changes
Purves et al. Neuroscience 2008,4th ed

50. Axon initial segment: the site of AP initiation
Contains a high sodium channel density
Contains high Ankyrin G protein density
Contains high Beta IV spectrin protein density
AIS sodium channels show a voltage dependence shifted to lower voltages
Alcami P & Hady AE. Frontiers in Cellular Neuroscience. 2019

51. Propagation of action potential

52. Passive electrical properties of nerve fiber
Membrane Resistance
Membrane Capacitance
Axial Resistance

53. An equivalent circuit of the neuronal
membrane
Kandel ER et al. Principles of Neural Science, 5th ed. 2013

54. Response of a true resistor
Step current
Change in the
voltage
OfInstantaneous change in the voltage after the
application of the current

55. Response of a true capacitor
Step current
Change in the
voltage
Delayed change in the voltage after the
application of the current

56. Time
Membrane capacitance slows rate of change in
the membrane potential
Kandel ER et al. Principles of Neural Science, 5th ed. 2013

57. Passive electrical properties of neuron affect
electrical signaling
Kandel ER et al. Principles of Neural Science, 5th ed. 2013
τ = membrane time constant
Rm = membrane resistance
Cm = membrane capacitance
Time constant

58. The time taken to reach 63% of the final voltage defines the
membrane time constant.
The time constants of different neurons typically range from
20 to 50 ms.
Membrane time constant

59. Kandel ER et al. Principles of Neural Science, 5th ed. 2013
Length
constant
ʎ = membrane length constant
rm = membrane resistance in a unit length of
dendrite

60. The change in V
m
decays exponentially with distance from the
site of current injection
The distance at which & V
m
has decayed to 37% of its value at the
point of current injection defines the length constant
Typical values for neuronal length constants range from
0.1 to 1.0 mm
Length Constant

61. Kandel ER et al. Principles of Neural Science, 5th ed. 2013

62. Electrotonic conduction contributes to
propagation of the action potential
Kandel ER et al. Principles of Neural Science, 5th ed. 2013

63. Nerve fiber
membrane
Speed of current flow
Less the axial resistance :
more is the flow rate
lower the membrane
capacitance:
more is the flow rate
Increase the diameter
myelination

64. Two ways to increase AP propagation speed
• Increase internal diameter of axon which decreases the internal
resistance to ion flow
• Increase the resistance of the plasma membrane to charge flow
by insulating it with myelin.

65. Myelin and Myelination
Myelin sheath are the layers of cell membrane of Schwann cells in the
peripheral nervous system and glial cells in the central nervous system

66. Chemical and physical nature of myelin
Made of proteins and lipid
Relatively rich in lipids (70 – 80%)
Cholesterol and sphingolipids is
high
Effect of myelination on the passive electrical properties of
nerve fiber
1. 5000 X increase in membrane resistance
2. 50 X decrease in membrane capacitance

67. Kandel ER et al. Principles of Neural Science, 5th ed. 2013
Is the membrane passive
What is the active component?
What happens at the node of
Ranvier?
saltatory
conduction

68. Action potentials propagate along the axon
with same amplitude
Constance Hammond. Cellular and Molecular Neurophysiology, 4th ed. 2015

69. Applied aspects
Genetic defects of Voltage gated channel
Hyperkalemic periodic paralysis
Nav1.4 muscle disorder
Paramyotonia congenita
Nav1.4 muscle disorder
Long QT syndrome
LQT1 & LQT2 – defects in voltage gated K+ channel
LQT3 – defects in domains 3 & 4 of Nav1.5
Boron & Boulpaep. Medical Physiology 2017,3rd ed

70. Thank You