Nerve physiology

The Nerve Physiology

© 2008 Paul Billiet ODWS

HISTORY

Joseph Erlanger(1874-1965) and Herbert Spencer Gasser (1888-1963)

1944 Joseph Erlanger and Herbert Spencer Gasser "for their discoveries relating to the highly differentiated functions of single nerve fibres

Joseph Erlanger and Herbert Spencer Gasser

Joseph Erlanger was an American physiologist Herbert Spencer Gasser was an American physiologist,

and recipient of the Nobel Prize for Physiology or Medicine in 1944 for his work with action potentials in nerve fibers while on the faculty of Washington University.

Erlanger and his student Gasser were interested in developing tools that could measure impulses fired through nerve cells, and they turned to the cathode-ray oscilloscope – an instrument that allows electrical currents to be visualized as a moving two-dimensional graph on a phosphorescent screen.

After its invention by Ferdinand Braun, the oscilloscope soon became the most effective tool for detecting rapid changes in electrical voltage, but still it was not sensitive enough to measure the weak and rapid electrical impulses that are fired along nerve cells

Eccles, Hodgkin and Huxley

The Nobel Prize in Physiology or Medicine 1963 was awarded jointly to Sir John Carew Eccles, Alan Lloyd Hodgkin and Andrew Fielding Huxley "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 and Huxley

Sir Alan Lloyd Hodgkin British physiologist and biophysicistSir John Carew Eccles, Australian neurophysiologistSir Andrew Fielding Huxley English physiologist and biophysicist,

Huxley evidenced the existence of saltatory conduction in myelinated nerve fibres. By showing how these impulses are generated and transmitted, the three scientists who received an equal share of the 1963 Nobel Prize in Physiology or Medicine revealed the key triggers that spark the nervous system's in-built electrical system into life. Seeking ways of measuring electrical currents inside nerves, Alan Hodgkin and his student Andrew Huxley turned to giant nerve fibres in the squid, which are almost a thousand times thicker than their human counterparts. Using tiny electrodes to record the electrical difference between the inside and outside of these nerves, they were surprised to find that the polarity did not drop from negative to zero during the transmission of an impulse as predicted, but in fact reversed, becoming electrically positive. By carrying out a series of measurements and using complex mathematical models to interpret the findings, Hodgkin and Huxley formulated a theory to propose how impulses are formed. Changes in the permeability of the cell membrane allow charged atoms to flow in and out of a nerve fibre, creating waves of electric charge that constitute the nerve impulse

Erwin Neher, Bert Sakmann

The Nobel Prize in Physiology or Medicine 1991 was awarded jointly to Erwin Neher and Bert Sakmann "for their discoveries concerning the function of single ion channels in cells"

Erwin Neher, Bert Sakmann

The two German cell physologisists Erwin Neher and Bert Sakmann have together developed a technique that allows the registration of the incredibly small electrical current (amounting to a picoampere-10-12A) that passes through a single ion channel. The technique is unique in that it records how a single channel molecule alters it's shape and in that way controls the flow of current within a time frame of a few millionths of a second.They have demonstrated what happens during the opening or closure of an ion channel with a diameter corresponding to that of a single sodium or chloride ion.

The neurone

Dendrites

Myelin sheath

Schwann cell Nucleus of Schwann cell

Axon

Nodes of Ranvier

Terminal dendrites

Experiments on the neurone of a giant squid

Ion

Concentration /mmol kg-1 water

Axoplasm (the cytoplasm

in an axon)

Blood plasma

Sea water

K+ 400 20 10

Na+ 50 440 460

Cl- 120 560 540

Organic anions

(-ve ions)360 - -


Cells and membrane potentials

All animal cells generate a small voltage across their membranesThis is because there is a large amount of small organic molecules in the cytoplasmTo balance this, animal cell pump Na+ out of the cellsThis regulates osmosis but it leaves a large number of organic molecules These are overall negatively changed (anions) in the cytoplasmThus the cell has a potential difference (voltage) across its membrane


Passive movement of ions across a cell membrane

The concentration gradient: causing the ions to diffuse down their concentration gradientThe electrical potential: causing ions to be attracted to the opposite charge to the one they carry


Potassium & Sodium Ions

The two important ions in a nerve cell (neurone or neuron) are K+ and Na+

Both are cations (positively charged ions)Na+ ions move more slowly across the membrane than K+ or Cl- ionsThis is because although the Na+ ion is smaller than the K+ ionNa+ has a larger coating of water molecules giving it a bigger diameterThis makes the plasma membrane 25 times more permeable to K+ than Na+


Potassium & Sodium Ions

In addition to this K+ ions leak out of K+ ion pores when the nerve cell is at restSo to maintain the high concentration of K+ inside the cell, it has to be actively pumped inwards a bit when the cell is at rest The result is that the resting potential of the neurone is almost at the equilibrium for K+ ions K+ leak out a bit and need pumping in Na+ ions, however, are actively pumped out and kept out


A coupled Na+-K+ pump

coupled ion pump

plasma membrane

K+

Na+

K+

Na+

Cytoplasm ECF


Ionic basis of EmNaK-ATPase pumps 3Na+

out for 2 K+ pumped in.Some of the K+ leaks back out, making the interior of the cell negative

Gated channels: ligand-gated

Gated channels: voltage-gated

Characteristics of the Nerve Impulse

An electrochemical event that occurs in nerve cells following proper stimulation.An all-or-none process which is fast acting and quick to recover.An event that is described by a voltage curve that is called an action potential.The nerve impulse can be conducted the entire length of a nerve cell without diminishment (“domino effect”).

Characteristics of a Nerve Impulse Continued:

The nerve impulse serves as the primary information signal used by the nervous system to provide communication about stimuli, nerve cell activity, neurotransmitter release and to generate various output responses (motor action, glandular secretion, etc.).Typically initiated by graded or generator potentials from a stimulus.

A change in potential that decreases with distance Localized depolarization or

hyperpolarization

Graded potential

Graded Potentials

Graded potentials vs Action Potential

PSPs vs APs

GradedSummation

longer duration*10-100 msec

chemical-gatedpassive spreadinstantaneousdecremental

All-or-none

short1-2 msec

voltage-gatedpropagatedslownondecremental

Resting Membrane Voltage (RMV)

Nernst Equation

By the end of the 19th century, it was known that the cytoplasm was high in K+ and that [Na+] was very low--and that this relationship was reversed outside the cell.

The assumption was made that the cell membrane was permiable to K+ but not to Na+.

Goldman equation was derived to solve for transmembrane potential using all ions involved simultaneously.

Resting membrane potential(MP) resting potential(RP)

•nerve, muscle negative, constant, cell typee.g.: warm-blooded animal: -55 to -100 mV; smooth muscle: -30 mV

Resting PotentialSodium/Potassium pump continuously and actively pumps (3) Na+ out of the cell and (2) K+ into the cell.

Na+ channels are closed so Na+ are not able to move into the cell.K+ channels are open so K+ can diffuse out of the cell.This generates a separation of charges so that the inside of the cell is relatively – and the outside is relatively +.The cell will remain in this state (at rest) until it is stimulated.

Inside of cell

Outside of cell

Depolarisation

Depolarising membranes may be achieved by:a stimulus arriving at a receptor cell (e.g. vibration of a hair cell in the ear)a chemical fitting into a receptor site (e.g. a neurotransmitter)a nerve impulse travelling down a neurone


Appears when region of excitable membrane depolarizes to thresholdSteps involved Membrane depolarization and sodium

channel activation Sodium channel inactivation Potassium channel activation Return to normal permeability

Action Potential

The Action Potential

Key Properties of the Action Potential Threshold Rising phase Overshoot Falling phase Undershoot Absolute refractory period Relative refractory period

Introduction

Action Potential in the Nervous System Conveys information over distances Action potential

Spike Nerve impulse Discharge

AP Characteristics

Voltage-gated channelsAll or noneSlowNon-decrementalSelf Propagated

The action potential

The action potential is the state of the neurone membrane when a nerve impulse passes byA small change in the membrane voltage will depolarise the membrane enough to flip open Na+ channelsThese are called voltage-gated Na+ channelsAs Na+ moves into the cell more and more Na+ channels openA small change in the membrane permeability to Na+ results in a big change in membrane potential


Properties of the Action Potential

The Ups and Downs of an Action Potential Oscilloscope to visualize an AP

Rising phase, overshoot, falling phase, and undershoot


The Generation of an Action Potential “All-or-none”: Cross threshold value

for action potential Chain reaction

Opens Na+-permeable channels Na+ influx depolarized membrane reaches threshold action potential


Firing frequency reflects the magnitude of the depolarizing current

Figure 2.16.1

The Generation of an Action Potential

Generation of action potential follows all-or-none principleRefractory period lasts from time action potential begins until normal resting potential returnsContinuous propagation spread of action potential across entire membrane in

series of small steps

Saltatory propagation action potential spreads from node to node, skipping

internodal membrane

Characteristics of action potentials

The Generation of an Action Potential

Induction of an action potential

Action potential propagationWhen the V-G Na+ channels open, they cause a depolarization of the neighboring membrane.This causes the Na+ and K+ channels in that piece of membrane to be activated

AP propagation cont.

The V_G chanels in the neighboring membrane then open, causing that membrane to depolarize.That depolarizes the next piece of membrane, etc.It takes a while for the Na+ channels to return to their voltage-sensitive state. Until then, they won’t respond to a second depolarization.

Propagation of an Action Potential along an Unmyelinated Axon

Saltatory Propagation along a Myelinated Axon

Action Potential Conduction

Propagation of the action potential Down axon to the axon terminal

Orthodromic: Action potential travels in one direction

Antidromic (experimental): Backward propagation

Typical conduction velocity: 10 m/sec Length of action potential: 2 msec


Factors Influencing Conduction Velocity Spread of action potential along

membrane Dependent upon axon structure

Path of the positive charge Inside of the axon (faster) Across the axonal membrane (slower)

Axonal excitability Axonal diameter (bigger = faster) Number of voltage-gated channels


Factors Influencing Conduction Velocity Myelin: Facilitates current flow Layers of myelin sheath

Myelinating cells Schwann cells in the PNS Oligodendroglia in CNS


Factors Influencing Conduction Velocity Saltatory conduction

Time

-70

-55

0

+35

Threshold

mV

Resting potential Action potential

More Na+ channels open Na+ floods into neurone

Na+ voltage-gated channels open


All-or-nothing

As Na+ moves in the cell will become more positive with respect to the outsideThe ion pumps resist the change in the membrane potential but it only has to rise by 15mV and the pumps cannot restore the equilibrium Na+ floods inNerve impulses all look the same, there are not big ones and little onesThis is the all-or-nothing law


All-or-None Principle

Throughout depolarisation, the Na+ continues to rush inside until the action potential reaches its peak and the sodium gates close.

If the depolarisation is not great enough to reach threshold, then an action potential and hence an impulse are not produced.

This is called the All-or-None Principle.

The threshold

–55mV represents the threshold potentialBeyond this we get a full action potentialThe membrane potential rises to +35mV this is the peak of the action potentialThe cells are almost at the equilibrium for Na+ ions


-70

-55

0

+35

Threshold

mV

Time

Resting potential Action potential

Na+ channels close and K+ channels open, K+ floods out of neurone

Resting potential© 2008 Paul Billiet ODWS

Potassium takes overAfter Na+ moves in passively until the Na+ channels start to closeAt the same time K+ permeability increases as voltage-gated K+ channels open – they are a bit slower to respond to the depolarisation than the Na+ channels The K+ ions move out This makes the cell negative inside with respect to outside againThe membrane potential falls


Hyperpolarisation

The membrane potential falls below the resting potential of –70mV It is said to be hyperpolarisedGradually active pumping of the ions (K+ in and Na+ out) restores the resting potentialDuring this period no impulses can pass along that part of the membraneThis is called the refractory period


-70

-55

0

+35

Threshold

Time

mV

Resting potential Resting potential

Action potential

Active pumping of Na+ out and K+ in during the refractory period

Hyperpolarisation of the membrane


Repolarization1. The sodium/potassium pumps return the cell to a resting state by actively pumping (3) Na+ out of the cell and (2) K+ into the cell.2. The K+ continues to diffuse out of the cell.

Refractory Periodafter AP won’t fire again relative & absolute

Relative during after hyperpolarization requires greater depolarization ~

Refractory PeriodThere are two types of

refractory period:Absolute Refractory

Period – Na+ channels are inactivated and no matter what stimulus is applied they will not re-open to allow Na+ in & depolarise the membrane to the threshold of an action potential.

Relative Refractory Period - Some of the Na+ channels have re-opened but the threshold is higher than normal making it more difficult for the activated Na+ channels to raise the membrane potential to the threshold of excitation.

Absolute refractory period

Na+ channels deactivate will not trigger AP must reset

CLINICAL IMPLICATIONS

Cellular ElectrophysiologyMembrane PotentialThe Na+ / K+ Pump

SEIZURE

Anti-seizure Medications

Seizures caused by hyperactive brain areasMultiple chemical classes of drugs All have same approach Decrease propagation of action

potentials Na+, Ca++ influx (delay

depolarization/prolong repolarization) Cl- influx (hyperpolarize membrane)

Anti-Seizure Medications

Benzodiazepinesdiazepam

(Valium®)lorazepam

(Ativan®)Barbituratesphenobarbital

(Luminal®)

Ion Channel Inhibitors

carbamazepine (Tegretol®)

phenytoin (Dilantin®)

Misc. Agentsvalproic acid

(Depakote®)

Clinical Correlation

It is the rate of action potential propagation that determines neurologic function.

Determined by frequency of action potentials.

What is a seizure?What is a seizure?

What would be the effect on the membrane

of Cl- influx during a seizure?

What would be the effect on the membrane

of Cl- influx during a seizure? Hyperpolarization & …

seizure activity!

Gamma Amino Butyric Gamma Amino Butyric Acid ReceptorsAcid Receptors

GABA ReceptorGABA

Receptor

Exterior

Interior

Cl -Cl -

Hyperpolarized!Hyperpolarized!

GABA+Bz ComplexGABA+Bz ComplexBz

ReceptorBz

ReceptorGABA

ReceptorGABA

Receptor

Exterior

Interior

Cl -Cl -

ProfoundlyHyperpolarized!

ProfoundlyHyperpolarized!

THANK YOU

Nerve physiology

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