Action Potential

General Education Program

Physiology 1

Presented by: Dr. Shaimaa Nasr Amin

Lecturer of Medical Physiology

Signal propagation in nerve cells

- Passive propagation: slow, decrease with distance,

summate.

- Active propagation: unlike wires, neurones also have

active electrical properties, triggered by changes in Vm.

These properties enable the conduction of electrical signals

without decrement over large distances.

Difference in signal propagation along a cable and along an axon

The signal gradually decreases away from the point of generation

The signal (action potential) does not change with distance

Neurones manage to transmit large signals in a fast and efficient way by generating action potentials which do not dissipate with distance along the axon

Action potentials are all-or-non signals

1. If the stimulus is too low there is no action potential (this is

the "none" part)

2. If the stimulus is above a threshold, the action potential is

always the same size- it does not get larger for stronger stimuli.

3. As the action potential travels along, it triggers the next

section of axon to fire.

Some terms that you need to understand and remember

0 mV

hyperpolarisation

depolarisation

repolarisation

overshoot

threshold

resting potential

-70 mV

+

-

excitability 1. Excitability 2. Depolarisation 3. Hyperpolarisation 4. Overshoot

means positive to 0 mV 5. Repolarisation

towards resting potential 6. Undershoot

means negative to the resting potential

7. Threshold (for action potential generation)

undershoot

Hodgkin and Huxley, in the 1950’s, developed a model to describe how a cell produces an action potential upon stimulation through interactions of voltage-gated Na+ and K+ channels.

The 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"

Sir John Carew

Eccles

Alan Lloyd Hodgkin Andrew Fielding Huxley

Australia Great Britain Great Britain

Australian National University

Canberra, Australia

Cambridge University Cambridge, Great

Britain

London University London, Great Britain

1903 - 1997 1914 - 1998 1917 -

Properties of the voltage-gated Na+ and K+ channels

• The axon membrane has voltage-sensitive Na+ and K+ ion channels.

• Na+ channels have both an internal (h) (inactivation) and external (m) (activation) gate. K+ channels have one gate, n.

http://courses.washington.edu/conj/membrane/nachan.htm

V-gated

Na+ channel

Properties of the voltage-gated Na+ and K+ channels

• What happens under resting conditions (~ -70 mV)?

• The internal Na+ h gate is open, but the external m gate is closed.

• The K+ gate n is closed as well. • Neither of these channels

therefore contribute to Vm under resting conditions.

• Vrest is close to EK and far from ENa.

When Vm decreases to threshold

External m gates of the Na+ channel start opening. Na+ ions flow inside the axon, causing a further decrease in Vm, which will result in more Na+ m gates opening. This sequence of events represents a positive feedback mechanism that leads to an explosive opening of more and more Na+ channels. This is the cause for the rising phase of the action potential.

Vm

gNa INa

What does this increase in sodium

permeability mean from the point of

view of the membrane potential

(Goldman equation)?

As a result of the positive feedback in Na+ current during the rising phase of the action potential…

…The increased Na+ permeability causes Vm to rapidly move towards ENa. The action potential overshoots and reaches its peak value.

What stops further depolarisation? 1. The internal h gates inactivate: they shut down because of the strong

depolarisation. 2. This rapid decrease in PNa prevents further depolarisation. Vm starts to repolarise,

returning towards EK. 3. The closing of h gates is what is responsible for the absolute refractory period.

Until these gates begin to open the membrane will not generate a second action potential.

Do you think that the sodium channel h

gates close at the same rate as m gates

open?

The role of K+ channels in the repolarisation of the action potential

Delayed K+ channels open (called delayed rectifier; n gates) - open after about 1-2 msec of threshold depolarisation - K+ flows out of the cell and speeds the repolarisation process

How would the action potential look like

if the voltage gated K+ channels were

blocked (cannot open)?

The undershoot of the action potential -Open delayed rectifier K+ channels make PK higher than at rest and membrane more negative on inside (voltage moves towards EK)

-Hyperpolarisation of membrane causes K+ channels to close (voltage-gated)

-Membrane settles back to rest

At the same time, the internal Na+ h gates re-open, and the membrane is ready to generate another action potential. These events are responsible for the relative refractory period.

Action potential Refractory period

a second AP CANNOT be produced, : Absolute refractory periodregardless of the stimulus strength

APs can be generated but with… : Relative refractory period 1. Increased threshold because have to overcome

hyperpolarisation 2. Reduced amplitude because fewer Na+ channels are

available to open (many are still in the inactive state) and so less Na+ can flow into the cell

Absolute Refractory period

The reason for this A.R.P. is that; during this

interval, Na+ channels are rapidly inactivated by

the inner gates .the period extends as long as

these gates are closed.

Relative Refractory Period [R.R.P]:

The relative refractory period begins when the

absolute refractory period ends and it terminates

when the membrane potential returns to its

resting level.

The cause of this R.R.P is two fold

1-Some of the Na+ channels have returned to their resting

state and are available for activation.

2-The k+ channels are usually wide open at this time

causing a state of hyper-polarization that makes more

difficult to stimulate the fiber.

Remember that:

A- Under resting conditions, all Na+ channels

are resting and ready for stimulation.

B- At beginning of depolarization, Na+ channels

start opening [activation]

Remember that:

C- At firing level, all channels are opened and

inactivation of Na+ channels starts.

D- At top of spike, all Na+ channels are

inactivated

E- At repolarization, Na+ channels start to

return to resting state.

The action potential always propagates forward

Why doesn’t it backfire?

- Depolarising current from the action potential can spread passively in either direction. - On one side (ahead of the AP), Na+ channels are in a closed state and are ready to be opened, therefore the spreading current can trigger an action potential in this neighbouring region. - On the other side (behind the AP), Na+ channels are in an inactive state and cannot be opened. Therefore the spreading current has no effect on the channels in this region and action potentials cannot be triggered.

The refractory period sets the direction of an action potential

Direction

of conduction

+ + + + + + + + + +

- - - - - - - - - - - -

- - - - - - - - - - - - -

+ +

+ +

- -

-

- +

-

+ +

-

+ + + + + + + + + + - + + +

refractory AP

axon

The myelin sheath

- In vertebrates, many axons are wrapped in a myelin sheath. - Myelin consists of several spiral layers (up to several mm thick) of

a specialised membrane made of 70-80% lipids and 20-30% proteins.

- Myelin is uniform and impermeable to movement of ions or other solutes.

- Short gaps, called nodes of Ranvier exist between the myelin sheaths, exposing the axon. The sheath between nodes is the "internode."

Signal propagation in myelinated axons

• Membrane areas covered by myelin do not become depolarised and therefore cannot generate action potentials.

• This forces the current to travel down the axon to the node of Ranvier where there is no myelin and the concentration of voltage-gated channels is high.

• Thus action potentials jump from one node to another. Between the nodes, there is passive spread of potential.

This process is called saltatory conduction (“saltare” means “jump” in Latin)

Functional consequences of saltatory conduction in myelinated axons

• Saltatory conduction significantly increases the conduction

velocity

• Small non-myelinated axons: conduction velocity is about 0.25

m/sec

• Large myelinated axons: conduction velocity can reach 120 m/sec

All or None law

The action potential obeys the all on none law.

That is action potential is either generated and

conducted maximally or not produced at all.

This is true regardless of the intensity of the

stimulus whether at or above the threshold

Intensity.

All or None law

This feature of action potential happens as

long as the other experimental conditions

remain constant.

Electrotonic Potentials and Local

Response

Although subthreshold stimuli do not produce an

action potential they produce electrotonic

potentials i.e changes in membrane potential that

do not propagate

Catelectrotonus

This is a state of passive depolarization produced

at the region of cathode.

The depolarization is less then 7 mV. The

negative current from cathode decreases the

membrane potential passively by the addition of

negative charges to the outer surface of the

membrane.

Anelectrotonus

This is a state of hyper-polarization produced at

the region of anode. It is produced by addition of

positive charges to the outer surface of the

membrane by the anode.

Local Response [Local Excitatory

State]

With stronger cathodal stimuli, slight active

changes occur and some Na+ activation gates

will open and contribute to the depolarizing

process, but the stimulus does not open enough

gates to elicit action potential.

Local Response [Local Excitatory

State]

The local response is graded i.e the magnitude

and duration of the local response vary with the

size and strength of the stimulus.

The local response does not obey All or None

law.

The local response is nonpropagated i.e its

magnitude is insufficient to generate another local

response near by and it fades a way within 1 - 2

mm.

During local response, the nerve excitability is

increased, as membrane potential moves

towards firing level.

Local Response [Local Excitatory

State]

The local response [which is caused by

subthreshold stimulus] can be summated i.e

another Simultaneous subthreshold stimulus may

act together producing higher depolarisation

which reach firing level and a new action potential

is elicited.

The local response has no refractory period.

Local Response [Local Excitatory

State]

Factors that affect excitability of the

nerve

A. Role of Na+:

1- Any condition that affect Na+ permeability will

affect membrane potential and nerve excitability.

a- Any condition that increases the permeability of

the membrane of the nerve fiber to Na+ causes the

nerve to be more excitable i.e. rapidly depolarized

e.g. vertarine and low Ca++ concentration in the

extracellular fluid.

Factors that affect excitability of the

nerve

• A. Role of Na+:

• b. High Ca++ concentration in the extracellular

fluid decreases the permeability of the membrane

of the nerve fiber to Na+ and decrease the

excitability.

Factors that affect excitability of the

nerve

• A. Role of Na+:

• c.Local anesthetics as cocaine decrease the

permeability of the membrane of the nerve fiber

to Na+, thus decreasing the excitability and the

nerve impulse fails to be produced. All the factors,

which decrease the excitability, are called

"membrane stabilizers".

Factors that affect excitability of the

nerve

• A. Role of Na+:

• 2- A decrease in ECF Na+ [hyponatremia]

decreases the size of the A.P. but has little effect

on R.M.P.

• 3- Blockade of Na+ channels by the toxin

tetrodotoxin [TTX] decreases nerve excitability,

and no A.P. could be elicited.

Factors that affect excitability of the

nerve

B. Role of K+

The resting membrane potential is primarily

dependent on the concentration gradient for K+.

Also, repolarization is caused by K+ exit.

Factors that affect excitability of the

nerve

B. Role of K+

1- Increase in extracellular K+ [hyperkalemia],

which makes the equilibrium potential for K+ more

positive, causes the membrane potential to

depolarize [i.e. become more positive] and

increases its excitability.

Factors that affect excitability of the

nerve B. Role of K+

2. Decrease in extracellular K+ concentration,

which causes the equilibrium potential for K+ more

negative, and causes the resting membrane

potential to hyperpolarize. This occurs in a

hereditary disease known as familial periodic

paralysis: the excitability of the nerves is greatly

reduced, no nerve impulses are produced and the

person becomes paralyzed. The condition is

treated by intravenous administration of K+ .

Factors that affect excitability of the

nerve

B. Role of K+

Blockade of K+ channels by tetraethylamonium

[TEA] will result in AP of longer duration due to

prolonged repolarization, but hyperpolarization is

absent

Factors that affect excitability of the

nerve

• C. Role of Na+ – K+ pump:

• At rest, the nerve membrane is relatively

impermeable to Na+, but depolarization phase of

A.P. is dependent on Na+ entry. Only a small

number of ions shares in ion exchange with each

nerve impulse, compared to the total number of

ions.

Factors that affect excitability of the

nerve

• C. Role of Na+ – K+ pump:

• The only prolonged blockade of Na+ K+ pump

would affect R.M.P. and genesis of A.P. in

excitable tissues.

Factors that affect excitability of the

nerve

• D. Electronic Potentials:

• During catelectrotonus and local response, the

threshold is lowered i.e. excitability is increased

as the membrane potential moves closer to the

firing level, and so a subthrshold stimulus may

produce an action potential.

Factors that affect excitability of the

nerve

• D. Electronic Potentials:

• During anaelectrotonus, threshold is elevated and

the membrane potential moves away from firing

level.

Accommodation of Nerve Fiber

• Gradual “slow” increase in intensity of a

subthreshold stimulus to threshold level will give

no response. The nerve is said to accommodate

itself to the passage of the current. If the intensity

of the current increases very rapidly,

accommodation is not observed.

Accommodation of Nerve Fiber

Accommodation is explained as follows

1. The slow activation “opening” of Na+

channels with subsequent slow entry of Na+

is balanced by:

• Inactivation “closure” of Na+ channels.

• Opening of K+ channels.

Nerve Fiber Types

. A fibers

The fibers of this group have a diameter between

2-20 microns. Their rate of conduction ranges from

20-120 m/sec. The duration of the spike is about

0.5 msec. The fibers of this group are further

subdivided on the basis of mean conduction

velocity and hence into fiber size into alpha, beta,

gamma and delta fibers.

Nerve Fiber Types

. B fibers:

The fibers of this group have a diameter between

1-5 microns. Their rate of conduction ranges from

5-15 m/sec. The duration of the spike is about 1.0

msec. The preganglionic autonomic nerve fibers

belong to this group.

Nerve Fiber Types

. C fibers:

The fibers of this group have a diameter less than

one micron. Their rate of conduction ranges from

0.5-2 m/sec. The duration of the spike is about 2.0

msec. The postganglionic autonomic nerve fibers

belong to this group.

Nerve Fiber Types

. C fibers:

In addition to variation in speed of conduction and

fiber diameter, the various classes of fibers in

peripheral nerves differ in their sensitivity to

anesthetics, pressure and hypoxia.

(1) Local anesthetics depress transmission in the

group C fibers before they affect A group fibers.

(2) Pressure on a nerve can cause loss of

conduction in A group fibers while C fibers remain

relatively intact.

(3) B fibers are most susceptible to hypoxia while

the C fibers are least affected.

Metabolism of Nerve

Under resting conditions, the nerve requires

energy mainly to maintain the polarization of the

membrane.

The energy for Na+-Ka+ pump is derived from the

breakdown of ATP.

Metabolism of Nerve

During activity Na+ accumulate inside the

membrane. Pump activity increases in proportion

to the third power of the Na+ concentration inside

the membrane i.e. if the Na+ concentration is

doubled the membrane Na+-K+ pump activity

increases approximately eight fold.

Nerve has a resting heat while inactive

Metabolism of Nerve

During activity, heat produced is increased:

a. An initial heat is produced during action

potential.

b. A recovery heat, which follows activity, the

recovery heat after a single impulse is about 30

times the initial heat.