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The Action PotentialThe Action Potential

Dr Sergey KasparovSchool of Medical Sciences, Room E9

Teaching home page:http://www.bristol.ac.uk/phys-pharm/personal/virallab/teaching/downloads.phpTeaching home page:http://www.bristol.ac.uk/phys-pharm/personal/virallab/teaching/downloads.php

Revision of the Resting membrane potentialRevision of the Resting membrane potential

1. Intracellular concentration of K+ is neurones is high and Na+ islow relative to the extracellular space2. The reversal potential is the potential towards which themembrane would move if it was freely permeable to thisparticular ion, and no other ions. At this potential chemicaldriving force is exactly equal electrical driving force and the netion flux in nill.

1. Intracellular concentration of K+ is neurones is high and Na+ islow relative to the extracellular space2. The reversal potential is the potential towards which themembrane would move if it was freely permeable to thisparticular ion, and no other ions. At this potential chemicaldriving force is exactly equal electrical driving force and the netion flux in nill.3. The reversal potential for K+ ions in neurones is very negative(~ -95 mV) while for Na+ ions positive (~ +60 mV).4. Resting membrane potential is generated mainly by a steadyflux of K+ ions through ion channels embedded into themembrane of the neurone.

3. The reversal potential for K+ ions in neurones is very negative(~ -95 mV) while for Na+ ions positive (~ +60 mV).4. Resting membrane potential is generated mainly by a steadyflux of K+ ions through ion channels embedded into themembrane of the neurone.

What is the action potential?What is the action potential?

AP is a brief “all-or-none” depolarisation of the neuronal membrane which, once initiated propagates without decrement. AP is a brief “all-or-none” depolarisation of the neuronal membrane which, once initiated propagates without decrement.

Movie - Nervous communication

0 mV0 mVAmplifierAmplifier

Real action potentialsReal action potentials

-60 mV-60 mVOne secondOne second

Action potentials are very fast changes in membrane potential from negative inside the cell to positive and back.Action potentials are very fast changes in membrane potential from negative inside the cell to positive and back.

Features of the AP – 1:

Propagation along the cell’s membrane and along the axon

Features of the AP – 1:

Propagation along the cell’s membrane and along the axon

AmplifierAmplifier Amplifier 1Amplifier 1 Amplifier 2Amplifier 2 Amplifier 3Amplifier 3

TimeTime

Amp 1Amp 1

Amp 2Amp 2

Amp 3Amp 3

Features of the AP – 2:

“All-on-none” natureFeatures of the AP – 2:

“All-on-none” nature

One secondOne second

In contrast to the “small, sub-threshold” potentials, action potentials have very similar amplitude and shape. Once the threshold has been reached, their amplitude will not increase even if a stronger stimulus is applied. In terms of information transfer they are like logic “ones”, as compared to “zeros”.

In contrast to the “small, sub-threshold” potentials, action potentials have very similar amplitude and shape. Once the threshold has been reached, their amplitude will not increase even if a stronger stimulus is applied. In terms of information transfer they are like logic “ones”, as compared to “zeros”.

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Glossary of the termsGlossary of the terms

Overshoot

Repolarisation

Resting membrane potentialResting membrane potential

Depolarisation

Repolarisation

Hyperpolarisation

Ionic basis of AP: Na ions are responsible for depolarisation, K ions are responsible for re-polarisation. Fluxes of both ions are coordinated by voltage-gated ion channels.

Ionic basis of AP: Na ions are responsible for depolarisation, K ions are responsible for re-polarisation. Fluxes of both ions are coordinated by voltage-gated ion channels.

Na+ channels are controlled by the potential of the membrane.Na+ channels are controlled by the potential of the membrane.

Extracellular domain

Extracellular domain

Aqueous poreAqueous pore

Lipid membraneLipid membrane

Voltage sensor and activation mechanismVoltage sensor and activation mechanism

Na+

Outside of the cellOutside of the cellNa+

Na+

Na+

Na+

Intracellular domain

Intracellular domain

Lipid membraneLipid membrane

“Inactivation gate”“Inactivation gate”

narrow selectivity filternarrow selectivity filter

Inside the cell (negative)Inside the cell (negative)

“Positive feedback” is responsible for the very fast dynamics of AP“Positive feedback” is responsible for the very fast dynamics of AP

1. Depolarisation 2. Opening of voltage-gated Na+ channels

3. Sodium currents depolarise membrane further

Something has to happen for this process to terminate!Something has to happen for this process to terminate!

At positive potentials voltage-gated Na+ channels become “inactivated” At positive potentials voltage-gated Na+ channels become “inactivated”

Extracellular domain

Extracellular domain

Aqueous poreAqueous pore

Lipid membraneLipid membrane

Voltage sensor and activation mechanismVoltage sensor and activation mechanism Outside of the cellOutside of the cellNa+

Na+Na+

Intracellular domain

Intracellular domain

Lipid membraneLipid membrane

“Inactivation gate”“Inactivation gate”

narrow selectivity filternarrow selectivity filter

Na+

Na+ Na+

Na+ current is responsible for the upstroke of the action potential

Na+ current is responsible for the upstroke of the action potential

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Ion channel activation during an Ion channel activation during an action potentialaction potentialIon channel activation during an Ion channel activation during an action potentialaction potential

--5050

5050

00

mVmV

REMEMBER:Na+ fluxes depolarise the membrane (EP ~+60),K+ fluxes hyperpolarise the membrane (EP ~-90)

REMEMBER:Na+ fluxes depolarise the membrane (EP ~+60),K+ fluxes hyperpolarise the membrane (EP ~-90)

--100100

NaNa++ channels openingchannels opening

KK++ channels openingchannels opening

NaNa++ channels channels inactivateinactivate

timetime

Two factors responsible for AP termination:

1. Inactivation of Na+ channels

2. Delayed activation of K+ channels (delayed rectifiers)

Two factors responsible for AP termination:

1. Inactivation of Na+ channels

2. Delayed activation of K+ channels (delayed rectifiers)

Molecular nature of the voltage-gated Na+ and K+ channelsMolecular nature of the voltage-gated Na+ and K+ channels

A voltage-gated Na channel is formed by association of 4 main (α) subunitsA voltage-gated Na channel is formed by association of 4 main (α) subunits

Refractory periodsRefractory periods

--5050

5050

00

mVmV

A) Absolute refractor period (second AP cannot occur under any circumstance)B) Relative refractory period (a stronger-than-normal stimulus may evoke an AP)A) Absolute refractor period (second AP cannot occur under any circumstance)B) Relative refractory period (a stronger-than-normal stimulus may evoke an AP)

Absolute Relative

NaNa++ channels openingchannels opening

KK++ channels openingchannels opening

NaNa++ channels channels inactivateinactivate

--100100timetime

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Saltatory conduction of AP, Schwann cells and oligodendrogliaSaltatory conduction of AP, Schwann cells and oligodendroglia

1. Axons of many types of neurones are “insulated” with multiple layers of myelin.2. Bare “gaps” between the insulated parts are known as nods of Ranvier.3. This is known as saltatory conduction. AP “jump” from one node to the next one as electrical field, rather than a wave of Na+ channel openings.4. This greatly accelerates AP propagation and saves much energy.

1. Axons of many types of neurones are “insulated” with multiple layers of myelin.2. Bare “gaps” between the insulated parts are known as nods of Ranvier.3. This is known as saltatory conduction. AP “jump” from one node to the next one as electrical field, rather than a wave of Na+ channel openings.4. This greatly accelerates AP propagation and saves much energy.

Saltatory conduction of AP, Schwann cells and oligodendrocytesSaltatory conduction of AP, Schwann cells and oligodendrocytes

Schwann cells are responsible for myelinisation in peripheral nervesSchwann cells are responsible for myelinisation in peripheral nerves

In the CNS myelin is provided by oligodendrocytesIn the CNS myelin is provided by oligodendrocytes

Speed of conductance depends on the degree of myelinisation. “Thick” vs “thin” axons.Speed of conductance depends on the degree of myelinisation. “Thick” vs “thin” axons.

1. Axons of different types of central and peripheral neurones have different degree of myelinisation.

2. Axons with thick myelin insulation are generally faster and can conduct at many tens of meters/second. Un-myelinated (or almost un-myelinated) axons can be as slow as 1 m/sec.

1. Axons of different types of central and peripheral neurones have different degree of myelinisation.

2. Axons with thick myelin insulation are generally faster and can conduct at many tens of meters/second. Un-myelinated (or almost un-myelinated) axons can be as slow as 1 m/sec.

3. Loss of myelin occurs in many diseases, for example multiple sclerosis. This may be fatal.3. Loss of myelin occurs in many diseases, for example multiple sclerosis. This may be fatal.

What happens at “the end” – action potentials lead to release of transmitter from pre-synaptic terminals.What happens at “the end” – action potentials lead to release of transmitter from pre-synaptic terminals.

Movie AP1

Movie Fancy neurones

Movie - Chemical synapse

Movie Fancy neurones

Summary

1. Features of AP2. Ionic basis of AP3. Basic mechanism of AP propagation3. Saltatory conduction and the role of myelin

Summary

1. Features of AP2. Ionic basis of AP3. Basic mechanism of AP propagation3. Saltatory conduction and the role of myelin