PHYSIOLOGY PRELIMS

MEMBRANE POTENTIAL AND ACTION POTENTIAL

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Dr. Gilbert Arendain AUGUST 12, 2024

OUTLINE ▪ Squid axon, measure the electrical conductance

across nerve fibers
I. Definitions of IV. Action Potential
Neurophysiology V. Structure of Cells
II. Diffusion and VI. III. ELECTRICAL POTENTIALS
Equilibrium VII. Action Potential ● BASIS OF WHY WE HAVE ELECTRICAL POTENTIALS
[Link] Potential vs. Graded Response → Vm
[Link] Equation VIII. Two Types of → Potential difference of the cell:
Refractory Period ▪ -70 mV (lecture);
▪ -94 mV (Guyton)
I. DEFINITIONS IN NEUROPHYSIOLOGY → Electronegativity of the cell
● Membrane potential or membrane voltage → What determines the electronegativity inside the
→ A concentration difference of ions across a selectively cell?
permeable membrane can produce a membrane ▪ Presence of anions and proteins contribute to
potential anionic charge
→ Refers to the difference of electrical charges across the ▪ Outside the cells, there are numerous cations
membrane → Sodium is a very versatile cation
→ All cells bear a potential difference across their ● Rules for ion movement:
membranes → From HIGHER to LOWER concentration
→ Electrical potentials exist across the membranes of → AWAY from LIKE charge (repulsion), TOWARD
virtually all cells of the body OPPOSITE charge (attraction)
→ There are a number of common synonyms for this → Depends on the membrane permeability (ability of ions
term: to traverse)
▪ “Diffusion potential,” ● Two most excitable cells:
▪ “Membrane potential,” and → NERVE cells
▪ “Electrical potential;” → MUSCLE cells
▪ They are used more or less interchangeably ● If you have a semipermeable membrane, only permeable
● Equilibrium Potential to sodium
→ Also called the Reversal Potential → Sodium goes from higher to lower concentration such
▪ is because the direction of ion flow will be in opposite that they equalize there will be no more net diffusion.
directions for potentials on either side of the → Electrical charges become 0 for both sides
membrane → Electrostatic forces to contend with; equilibrate the
→ Is the diffusion potential that exactly balances or electrical charges as well.
opposes the tendency for diffusion down the → Concentration difference of Sodium:
concentration difference. At electrochemical ▪ Outside: 135-145 mmol/L
equilibrium, the chemical and electrical driving forces ▪ Inside: 12-15 mmol/L
acting on an ion are equal and opposite, and no further → Sodium has the potential to go in; however, the
net diffusion occur potential for sodium to go out is positive
→ From 150mM to 15mM, the direction will therefore be
Additional information: towards intracellular fluid
● Claude Bernard → Equilibrium potential for different ions:
→ Father of Modern Physiology ▪ Na: +61 mV
→ French physiologist; internal environment was coined ▪ K: -94 mV
→ Father of modern physiology ▪ Cl: -70 mV
→ Coined the term milieu intérieur (internal environment) → There is a big difference between concentrations of Na
and K inside and outside the cell, and it has to be
maintained the way
II. DIFFUSION AND EQUILIBRIUM ● NaK ATPase pump is electrogenic
→ It maintains the -70mV interior of cells
● What is the difference between diffusion and
→ Uses integral proteins
equilibrium?
→ 3 Na out, 2 K in
→ Diffusion is occuring in order to restore equilibrium
→ Net effect: The inside of the cell becomes more
→ Equilibrium is the state of being balanced, while
negative than outside
diffusion is something that is occurring
● Cell Volume Surveillance
▪ Equilibrium is not balanced: “Steady state”
→ When Na goes into the cell, water will follow
▪ Equilibrium is costly to maintain, in terms of ATP
→ If the cell swells, Na/K ATPase pump is activated to
prevent cell lysis
Additional information:
● Early electrophysiology experiments by Galvani
→ Connected the frog and waited for a lightning to strike
Nernst Equation
to measure electrical connections ● Describes the relationship of diffusion potential to the ion
→ Refined by Goldman, Hodgkin, and Katzin (1943) concentration difference across a membrane
▪ Won the nobel prize for the experiment of the squid ● Nernst Potential
axon

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→ The diffusion potential across a membrane that exactly

opposed the net diffusion a particular ion through the IV. ACTION POTENTIAL
membrane ● Neuron Action Potential:
→ The magnitude of the Nernst potential is determined by → Resting stage
the ratio of the concentration of that specific ion on the → Depolarization stage
2 sides of the membrane → Repolarization stage
→ The greater this ratio, the greater the tendency for the ● Electrical Excitability and Action Potentials
ion to diffuse in one direction and therefore the greater → Cells with this property:
Nernst potential required to prevent additional net ▪ depolarize the membrane above a threshold voltage
diffusion → triggers a spontaneous all-or-none response →
𝐸𝑀𝐹 = ± 61 𝑙𝑜𝑔( 𝐶2 )
𝐶1 action potential
● Action Potential
→ Electrical impulse
𝑅𝑇 [𝑋] 𝑒𝑥𝑡𝑟𝑎𝑐𝑒𝑙𝑙𝑢𝑙𝑎𝑟
𝐸= 𝑧𝐹
𝑙𝑛( [𝑋] 𝑖𝑛𝑡𝑟𝑎𝑐𝑒𝑙𝑙𝑢𝑙𝑎𝑟 ) → Transient
→ Where EMF is the electromotive force in millivolts → Regenerative
→ X is the charge particle → Membrane potential (Vm) rapidly rises to a peak that is
→ R is universal gas constant ~100 mV more positive than normal, negative resting
→ T is temperature in Kelvin voltage (Vrest)
→ z is the electrical charge of the ion (valence) → Such signals, also called spikes → propagate for long
→ F is Faraday’s constant (not mentioned) distances along nerve or muscle fibers
→ ln is natural logarithmic ● Plateau in some action potentials
→ The excited membrane does not repolarize immediately
Goldman Equation after depolarization; instead, the potential remains on a
● Goldman equation is used to calculate the diffusion plateau near the peak of the spike potential for many
potential when the membrane is permeable to several milliseconds before repolarization begins.
different ions → the cause of the plateau is a combination of several
→ Multiple several ions factors
▪ first, in heart muscle, two types of channels
When a membrane is permeable to several different ions,, contribute to the depolarization process
the diffusion potential that develops depends on three 1. the usual voltage-activated Na channels, called fast
factors: channels; and
1. The polarity of the electrical charge of each ion; 2. voltage-activated Ca-Na channels (L-type Ca
2. The permeability of the membrane (P) to each ion; channels), which are slow to open and therefore are
and called slow channels.
3. The concentration (C) of the respective ions. → Opening of fast channels causes the spike portion of
the action potential, whereas the prolonged opening of
Thus: this equation… the slow Ca-Na channels mainly allows Ca ions to
→ gives the calculated membrane potential on the inside of enter the fiber, which is largely responsible for the
the membrane when two univalent positive ions, sodium plateau portion of the action potential
(Na+) and potassium (K+), and one univalent negative ion,
chloride (Cl-), are involved:

Key points in Goldman Equation:

1. Sodium, potassium, and Chloride ions are the
most important ions involved in the development of
membrane potentials in nerve and muscle fibers, as
well as in neuronal cells.
2. The quantitative importance of each of the ions in
determining the voltage is proportional to the
membrane permeability for that particular ion.
3. A positive ion concentration gradient from the inside
membrane to the outside causes electronegativity in
the cell membrane.
4. The permeability of the sodium and potassium
channels undergoes rapid changes during
transmission of a nerve impulse, whereas the
permeability of the chloride channels does not
change greatly during this process. Therefore: rapid
changes in sodium and potassium permeability are
primarily responsible for signal transmission in
neurons.

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RESTING MEMBRANE POTENTIAL degree of negativity (@-4 millivolts additional) on

the inside, beyond that which can be accounted
for by diffusion alone.
▪ Therefore – the net membrane potential when all
these factors are operative at the same time is
about -90 millivolts.
→ Role of the Na-K-ATP pump
▪ Re-establishing Na and K ionic gradients after
action potentials are completed - importance of
energy metabolism
▪ The Na-K-ATP pump degree of activity is strongly
stimulated when excess sodium ions accumulate
→ Begins at resting membrane potential: -70 mV inside the cell membrane; the recharging process
→ Rising phase of action potential: Cell stimulation of the nerve fiber can be set rapidly into motion
occurs, the threshold is exceeded: -55 mV whenever concentration differences of Na and K
→ All or nothing; if -55mV is not reached, no action ions across the membrane begin to run down.
potential will be transmitted.
→ Depolarizing stimulus
→ Peak is +10 mV to +40 mV depending on the V. STRUCTURE OF NERVE CELLS
myelinated nerve ● Dendrites - receives signals
→ Repolarization Phase: ● Axon - transports electrical impulse
▪ After the peak, it goes down. ● Soma/Cell body - processing
▪ Broken line is defined as the brief spike: after the ● Axon terminal - electrical potential is transported to the
peak it goes down immediately axon terminal, where another dendrite may be located
▪ Orange line; plateau phase Additional information:
▪ Due to another ion (Calcium ions)
▪ The part of the action potential that lies above 0 mV ● Nerve
is called overshoot. [the time course and shape of → Combination of many axons
the repolarization phase vary considerably among ● Nerve Trunk
different excitable tissues and cells. → Combination of nerves
→ Hyperpolarization phase:
▪ Membrane potential will go beyond resting (-80mV)
▪ More negative than the resting potential VI.
▪ As time goes by it will go back to resting and ready ● Chemical and Electrical Gradient
for another stimulation or action potential → Maintenance of both gradients inside and outside the
→ Undershoot is the figure under 0. cells (Electrochemical gradient)
● Sodium and potassium have leaky channels in the cell
● Origin of the normal resting membrane membrane
→ Contribution of the Potassium Diffusion Potential. ● Sodium ions only pass through sodium ion channels and
▪ Because of the high ratio of potassium ions inside voltage gated ion channels.
to outside, 35:1, the Nernst potential ● Voltage gated ion channel - opens based on electrical
corresponding to this ratio is -94 millivolts voltage
because the logarithm of 35 is 1.54, and this, ● Mechanically gated ion channel - opens upon pressure or
multiplied by -61 millivolts, is -94 mv. touch
▪ Therefore: if potassium ions were the only factor ● Ligand-gated ion channel- opens depending on the ligand.
causing the resting potential, the resting potential - Ex. Acetylcholine activates the channel by binding
inside the fiber would be equal to -94 m.v to the binding site outside the cell.

VII. ACTION POTENTIAL VS. GRADED

RESPONSES
● Graded potential
→ Also known as Subthreshold potentials
→ Action potentials that does not reach the threshold
value, thus not exhibiting an action potential
→ Excitatory postsynaptic potentials (EPSPs); if it is an
inhibitory signal, which makes it less negative , it will be
called inhibitory postsynaptic potentials (IPSPs).
→ But sometimes, summation may occur wherein
→ Contribution of the Na+-K+ Pump. barrage of ESPS may summate and reach threshold,
▪ Continuous pumping of 3 sodium ions to the thus firing an action potential.
outside occurs for each 2 potassium ions pumped → Processed in the axon hillock
to the inside of the membrane. ▪ Between cell body and axon
▪ Pumping of more sodium ions to the outside than Why is the all or none process here? Because axon
the potassium ions being pumped to the inside → hillock has the most number of voltage-gated ion
causes continual loss of positive charges from channels.
inside the membrane, creating an additional ● Graded Response and Action Potentials
→ Differ from one cell to another at one particular site

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→ Also behave differently in the way they spread along → A sudden rise in membrane potential of 15 to 30
the membrane from the site of origin millivolts is usually required
→ As graded response spreads; its magnitude decays → therefore: a sudden increase in the membrane potential
exponentially with the distance from the site of in a large nerve fiber, from -70 millivolts up to about
stimulation because of loss of energy to the medium -55 millivolts usually causes the explosive
▪ This decay is called electronic conduction. development of an action potential
● 3 States of Sodium Channels: → This level of -55 millivolts is said to be the threshold
→ Open for stimulation.
→ Close
→ Inactivated; done intracellularly VIII. REFRACTORY PERIOD AFTER AN
▪ The voltage gated ion channels may be opened at ACTION POTENTIAL, DURING WHICH A
the exterior side but it may be blocked or closed at
the interior side NEW STIMULUS CANNOT BE ELICITED
● During depolarization ● A new action potential cannot occur in an excitable fiber
→ During the initiation, resting, then nerve stimulation,(?) as long as the membrane is still depolarized from the
when that happens there will be inrush of sodium ions preceding action potential.
from the outside to inside through the voltage gated ion ● The reason for this restriction is that shortly after the
channels action potential is initiated, the sodium channels (or
→ However it depends on the strength of the stimulus e.g. Calcium channels or both) become inactivated, and no
subthreshold = no action potential amount of excitatory signal applied to these channels at
→ If > threshold = action potential will be generated (rising this point will open activation gates.
phase of depolarization) ● The only condition that will allow them to re-open is for the
→ Depolarization means reversal of charges lining the cell membrane potential to return to or near the original resting
membrane upon initiation of stimulus. membrane potential level.
→ The outside is lined by positive charges ● Then, within another small fraction of a second, the
→ The inside is lined by negative charges inactivation gates of the channels open and a new action
→ Voltage gated ion channels inactivate at the peak of potential can be initiated.
depolarization
- Opening of voltage-gated sodium ion channels > IX. TWO TYPES OF REFRACTORY PERIOD
Inrush of sodium ions > It reaches the peak > ● Absolute Refractory Period
Inactivates (blocked from inside) > Repolarization → In the axon hillock
→ Repolarization occurs via voltage-gated potassium ion → At this period a second action potential cannot be
channels. Immediately after the peak of depolarization elicited, even with strong stimulus.
→ During repolarization, voltage-gated potassium ion → Large myelinated nerve fibers in this period are about
channels start to open SLOWLY. Cation goes out; 1/2500 second.
making the inside of the cell MORE negative. → Therefore, one can readily calculate that such fiber can
- Recall: Depolarization makes the inside of the cell transmit a maximum of about 2500 impulses per
LESS NEGATIVE due to sodium ions (don’t use the second.
term positive). ▪ There can be no superimposition of another action
→ What happens when it reaches resting going to potential in this phase regardless of strength of
hyperpolarization: stimulus
▪ Voltage-gated potassium channels are still open; no ● Relative Refractory Period
sodium coming in, but potassium ions continue to go → At this point (during the falling phase), most of the
out. voltage gated ion channels have already closed, thus
▪ Removal of cations inside the cell results in they may be capable of opening again
hyperpolarization (going below -70). → A second response can be elicited but requires a
▪ However, as potassium channels close, it will go up stronger stimulus.
back again to resting membrane potential (-70), yet - Because most of the voltage-gated sodium ions are
again ready for another action potential. closed and may only be opened by stronger
● Step of Action Potential Generation stimulus.
1. Resting membrane potential ● Stimulus lower than threshold may reach the threshold if
2. Stimulation it remains consistent. Regardless of strength, stimulation
3. Rising phase at depolarization, opening of voltage may reach the threshold depending on its continuity.
gated ion channels ● Generation/propagation of action potential is dependent
4. - peak on the status of axons- Myelinated or unmyelinated.
5. Falling phase or repolarization via the slow opening of - Action potentials travel faster in myelinated
gated potassium channels axons.
6. Overshoots (goes below the -70) ● Depending on the stimulation, there is more stimulation of
7. Back again to Vrest (step 1) the nerves
● Initiation of the action potential occurs only after the → However if the stimulation is weak, GOOD FEELING?!
threshold potential is reached HAHAHAHAHAHA
→ An action potential will not occur until the initial rise in ● Saltatory Conduction
membrane potential is great enough to create the → Myelin sheaths that covers the axon which acts as an
positive feedback insulator
→ This occurs when the number of Na ions entering the → Size of the axon is also considered
fiber is greater than the number of potassium ions (Bigger nerves=faster propagation)
leaving the fiber. → This happens in myelinated axons

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→ “Saltatory”: It travels along nodes of Ranvier; faster → No NaK channels closed; already opened and
propagation underwent repolarization during the action potential
▪ In PNS, myelin (fatty layer of axon) is due to the propagation.
schwann cells → Hence it is only unidirectional.
▪ In CNS, it is made by oligodendrocytes.
● Action potential propagation is slow, myelin sheaths make
conduction faster via saltatory conduction
● Propagation of the action potential
→ Direction of Propagation - an excitable membrane has
no single direction of propagation, but the action
potential travels in all directions away from the
stimulus - even along all branches of a nerve fiber -
until the entire membrane has become depolarized.
● Types of Stimulus
→ Hyperpolarizing stimulus; tracing reflects the strength of
stimulus.
→ Hyperpolarizing stimulus: tracing is going downward.
→ Depolarizing stimulus: the tracing is going up and it
reaches the threshold.
→ Red line is representative of the strongest stimulation.
→ Brown is subthreshold stimulation.

● Re-Excitation Process Necessary for Spontaneous

Rhythmicity.
→ For spontaneous rhythmicity to occur, the
membrane - even in its natural state must be
permeable enough to sodium ions (or to calcium
and sodium ions through the slow calcium-sodium
channels) to allow automatic membrane
depolarization.
→ the resting membrane potential in the rhythmical
control center of the heart is only
→ -60 to -70 millivolts, which is not enough negative
voltage to keep the sodium and calcium channels
totally closed.
→ Therefore, the following sequence occurs:
(1) some sodium and calcium ions flow inward;
(2) this increases the membrane voltage in the
positive direction, which further increases
membrane permeability:
(3) still more ions flow inward; and
(4) the permeability increases more, and so on, until
an action potential is generated.
● Respond to Stimuli as a function of Distance
→ If you stimulate at one point and place electrodes Saltatory Conduction in Myelinated Fibers from Node to
equidistant to each other along one direction, we can Node.
see a recording of the propagation of action potentials
→ If hyperpolarizing stimulus, downward deflection ● Saltatory conduction is of value for two reasons:
→ There is no propagation of action potential because it → causing the depolarization process to jump long
decays (electrotonic conduction) intervals along the axis of the nerve fiber, this
→ In contrast to depolarizing stimulus: mechanism increases the velocity of nerve
▪ From electrode 1 - 4, the action potential is transmission in myelinated fibers as much as 5-to
propagated 50-fold.
▪ Magnitude of the stimulus will remain the same. → Saltatory conduction conserves energy for the axon
▪ The difference lies in the arrival of stimulus because only the nodes depolarize, allowing 100
▪ Delay is because in relation to the distance from the times less loss of ions than would otherwise be
stimulus necessary, and therefore requiring much less
▪ But it can be assured that the action potential will energy expenditure for re-establishing the sodium
reach its target tissue and potassium concentration differences across the
▪ It’s just that there’s quite a delay across time, unlike membrane after a series of nerve impulses.
in a hyperpolarizing stimulus. (Saltatory conduction) ● Velocity of Conduction in Nerve Fibers.
● Why is the arrow going forward? Can it also go in the → The velocity of action potential conduction in nerve
opposite direction? fibers:
→ Unidirectional because repolarization is already going → varies from as little as 0.25 m/sec in small
on as the impulse is being propagated to one direction unmyelinated fibers to as much as ...
→ 100 m/sec-more than the length of a football field in
1 second-in large myelinated fibers

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X. INHIBITION OF EXCITABILITY— LOCAL

ANESTHETICS
● In contrast to the factors that increase nerve excitability ,
membrane stabilizing factors can decrease excitability.
→ For example: a high extracellular fluid calcium
ion concentration decreases membrane
permeability to sodium ions and simultaneously
reduces excitability.
● Procaine and Tetracaine
→ most important stabilizers used clinically as local
anesthetics.
→ Most of these agents act directly on activation gates
of the sodium channels → making it much more
difficult for the gates to open and thereby reducing
membrane excitability.
→ When excitability has been reduced so low that the
ratio of action potential strength to excitability
threshold (safety factor) is reduced below 1.0 →
nerve impulses fail to pass along the anesthetized
nerves.

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INDEX: APPENDIX