01 Neuronal Function

7/27/2019 01 Neuronal Function

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The Physiology of Neuronal

Functionsneuronal morphologyneuronal circuits

membrane potentials

passive electrical properties of

membranes

electrochemical potentials

the generation of the membrane

resting potential

stimulation of the action potential

ionic basis of the action potential

the voltage-gated Na+channel

References: p. 113-128; 131-137


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Central nervous system (CNS): neurons of the brainand

the nerve cord(the spinal cord in vertebrates)Peripheral nervous system (PNS): neurons that connect

the CNS to all target tissues

Nervous systems


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Morphology

of neurons

All neurons have the

soma, one axon, and

numerous dendrites. Thecomplexity of structure

is related to function,

not phylogeny.


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Neuronal morphology

Soma

cell body

site of metabolism and cell

maintenance

may receive stimuli from

other neuronsDendrites

extensions of the soma

receive stimuli

receive signals form otherneurons

typical neuron can have

100s-1000s


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Axonconducts signals away from the cell body and toward the

axon terminal

only one per neuron

may branch at the axon terminalduring the development of the nervous system: the axon

extends from the soma toward the target cell(s) following

migratory cues

when the target is reached, specific junctions are formed

Neuronal morphology


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Cell body extensions and their interactions with other cells

establish a cell polarity:

dendrites: toward somaaxon: away from soma

Neuronal polarity

Example: skin mechanoreceptors (touch receptors) signals

travel from dendrites near skin to soma, then from soma

to axon terminals near the spinal cord (next illustration)


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Transmission of signals

between neurons in a

simple neuronal circuit

Sensory neurons (afferent neurons):

receive external stimuli and

transmit them to the CNS.

Interneurons: connections withinthe CNS.

Motor neurons (efferent neurons):

relays the signal to the tissue

that will elicit the response.


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A simple neuronal circuit

The ref lex arch in the cockroach:

afferent neuron: wind receptor

a giant interneuron

within the CNS

efferent neuron: leg

motor neuron

Note: locations

of the soma.


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In any neural connection there

is a presynaptic cell (the neuron

that transmits the signal) and a

postsynaptic cell (thetarget,

which may be another neuron ora different cell type).

Transmission of electrical

signalsbetweenneurons

Synapses: the junctions between

both cells.


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Graded signals: through thesomavary in amplitude

the strength of the signal depends

on the strength of the stimulus

lose intensity as they propagateAll-or-none signals:through the

axon

invariant amplitude

initiate in response to graded signals

once initiated, they propagate down

the axon without loss of signal

intensity


signalswithin neurons


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The dendrites and the soma receive neurotransmitters

(chemicalsignals)from presynaptic terminals (the axon

terminals from presynaptic neurons).

chemical signals are then converted into electrical signals

when ion currents in the synapse region flow into the cell

these ion currents (graded signals) travel through the somaand are integrated at the spike initiation zone

the neuron then initiates its own electrical signal: the action

potential (AP, an all-or-none signal)

the action potential then travels down the axon and away

from the soma without losing its intensity

the signal reaches the axon terminal

the signal is converted back into a chemical signal when a

neurotransmitter is secreted into the next synapse

Transmission of electrical signalswithinthe neuron


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signalswithin neurons

The neurons ability to transmit

a graded signal depends on the

passive electrical properties of

its membrane. The neurons

ability to initiatean all-or-nonesignal, and its ability to transmit

it withoutsignal loss, depend

on the active electrical properties

of its membrane.


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The nature of electrical signals in neurons

Electric potential:

the concentration of ions on one side of the membrane

electrostatic force:potential energy(why?)

Membrane potential:

the difference in ionic electric potentials between the two

sides of a membrane

Result: a voltage across the membrane (Vm), measured in

millivolts (mV)


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The ion gradients across the membrane

of a typical mammalian cell

The ion gradients across the membrane maintains osmotic

balance and are also necessary for many physiological

functions.


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Membrane-targeted antibiotics transport ions across the cell

membrane and destroy ionic gradients that are essential to

the life of the cells

Ionophores:

Valinomycin is a small ring molecule that binds K+in its

hydrophilic interior, shielding its charge from the

surrounding environmentthe outside region of the molecule is nonpolar, thus

facilitating its crossing of the hydrophobic interior of the

lipid membrane

Channel formers:Gramicidins are dimers of linear peptides that insert

themselves into lipid bilayers and allow the free passage

of H+, K+, and Na+ions


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Cystic fibrosis

Cystic fibrosis is caused by a mutation in an ATP-dependent

Cl

-

transport, which alters the normal ionic gradients inseveral types of epithelial cells.

this results in the abnormal production of thick, sticky

mucous secretions by epithelial cells lining the

respiratory and intestinal tracts (Why?)treatment may extend the survival of affected individuals to

about 30 years, but the disease is ultimately fatal, with

lung disease being responsible for 95% of mortality


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The ATP-dependent Cl-

transport

70% of the point mutations

that cause cystic fibrosis

disrupt the folding of the

protein, resulting in

defective Cl-

transport.


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Na+,K+,Ca2+, and Cl-gradients maintain membrane

voltages in all living cells, but:

only two types of cells are able to respond to changes in

membrane voltage: neurons and muscle cells

only neurons and muscle cells areexcitable cells

The voltage across a membrane


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Luigi Galvani

(1737-1798)

Italian physicist

i i l i i ( )


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Luigi Galvani was looking for the animal electr ici tythat

activated the muscles of his dissected frog specimens.

he devised an electrical circuit: a muscle cell touched by a

nerve and a zinc rod, and a different metal rod (cooper)

that linked the nerve and the zinc rod (a)

he then observed that muscle cells contracted when the twodissimilar rods touched (circuit completed)

Alessandro Volta (1792) suggested that the metal rods

provided an outside energy source that excited the cells

Carlo Matteucci demonstrated that excitable tissues produce

electric currents (b)

Luigi Galvanis experiments (1791)

i i G l i i (1 91)


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Luigi Galvanis experiments (1791)

C l M i i


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Carlo Matteuccis experiments

M i b i l


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Vmcan be recorded as the difference in electric potentials

detected by a recording glass microelectrode and a

reference electrode.

no difference when both electrodes are in the saline bath

Measuring membrane potential

M i b t ti l


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when the recording electrode penetrates cell, the difference

in electric potentials between the two sides of themembrane is recorded as a voltage (Vm)

Vm(membrane voltage) of living cells have negative values:

higher concentration of negative ions on the cytosolicside

of the membrane (inside the cell)

Measuring membrane potential

M b t ti l


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Membrane potential

The membrane potential of living cells is defined as the

cytosolic potential relative to the extracellular potential

(extracellular potential is conventionally defined as zero).

steady inside-negative potential: resting potential (Vrest)

all cells have a Vrestbetween -20 mV and -100 mV

due to the passive electrical properties of the membran

P i l t i l ti f th ll b


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Electrical Resistance (R): impermeability to ions.

Electrical Conductance (g): permeability to ions due to open

ion channels.

Passive electrical properties of the cell membrane

the resistive current (Ir) will be higher if R is low (when ion

channels open)

R=1/g

P i l t i l ti f th ll b


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Capacitance: the ability to store electric charges (Cm).

the lipid bilayer is impermeable to ions but is very thin,

therefore:

ionic charges on both sides of the membrane can interact

if there is an excess of positive charges on the extracellular

side: they will be displaced toward the membrane, theywill attract anions on the other side, and cations on the

cytoplasm will be repelled from the membrane

effect: a capacitative current (Ic)

Passive electrical properties of the cell membrane

Th ll b it


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Capacitance: CmCapacitative

current: Ic

The cell membrane as a capacitor

Membrane oltage changes in response to


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Membrane voltage changes in response to

stimulating currents

Stimulus current: an ion flow through the cell membrane that

can change its resting potential.

this current can be experimentally applied using a current

electrode

Membrane voltage


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Membrane voltage

changes in response to


Deviations from the resting

potential in response

to applied currents:

small negative stimuluscurrent: a small

hyperpolarization of

the membrane (1 & 2)

smallpositive stimulus

current: a small

depolarization of

the membrane (3)

Membrane voltage


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But:

if Vmreaches the

threshold potential:

an action potential(AP) is fired(4)

Membrane voltage



(this happens only

in excitable cells)

Membrane voltage


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Whats wrong with

this figure?

The DVmresulting from

a subthreshold stimulusshould be sustained for

as long as the stimulus

current is applied.

Membrane voltage



Passive electrical properties of the membrane


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capacitance and conductance/resistance are the passive

electrical properties of the membrane

they give the membrane its ability for time-dependent

responses to stimulation and voltage changes

they depend on the membrane potential (Vm)

Summary

How is the membrane potential generated?

Passive electrical properties of the membrane

Electrochemical potential


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Electrochemical potential defines the potential difference

across the plasma membrane. It is dependent on two

features of cells:

1. the concentrations of certain ions on the cytosolicside

of the membrane are different from the extracellular

side of the membrane2. membranes are selectively permeable to ions due to

the presence of selective ion channels

Electrochemical potential

A chamber filled with KCl with two compartments separated


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A chamber filled with KCl, with two compartments separated

by a membrane that is permeable to K+but notto Cl-

equal movement of K+in both directions but no net

changes in K+concentration

equal distribution of charges: no potential difference (Vm=0)

If KCL concentration in compartment I is increased


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If KCL concentration in compartment I is increased

K+will tend to move to compartment II (due to the K+

concentrationgradient)

this will generate a K+gradient and a voltage across the

membrane

the resulting electromotive force (emf) will tend to drive K+

back to compartment I

when no more net K+flow occurs: electrochemical

equilibrium, due to both driving forces, which occurs

at the equilibrium potential

If KCL concentration


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If KCL concentration

in compartment I

is increased

Summary of definitions


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Summary of definitions

Electrochemical equilibrium:

the state at which the concentration gradient of an ion acrossa membrane is precisely balanced by the electromotive

force across the membrane in the opposite direction

not netflow of the ion occurs

it is notthe state in which the concentrations of the ion onboth sides of the membrane are equal

Equilibrium potential (Ex):

the Vmat which an ionic species that can diffuse across the

membrane is in electrochemical equilibrium

example: the equilibrium potential for K+isEK

The generation of the membrane potential


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The resting membrane potential (Vrest) in cells is

maintained at the expense of metabolic energy.

because of this, Vrestis a steady state potential (not an

equilibrium potential)

Vrestgives the membrane itspassiveelectrical properties(capacitance and conductance/resistance)

The generation of the membrane potential

in biological membranes

Generation of the membrane resting potential


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Generation of the membrane resting potential

The ions channels responsible for the steady state potential

are the Na+/K+pump(requires energy) and the

K+leak channel(does notrequire energy).

The Na+/K+pump

hydrolyzes ATP to transport 3 Na+s out of the cell

and 2 K+s to the cytoplasmresult: unequal ionic distribution (an electrochemichal

gradient)

The K+

leak channelallowssomeK+to flow back through the membrane

determined by:

1. concentration gradient (K+inside)

2. electrical gradient (Na+emf from outside)

The Na+/K+


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The Na /K

pump generates

the membrane

resting potential

Active electrical properties of the membrane


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Active electrical properties of the membrane

The action potential

The action potential(AP) is a sudden and transient changein the cell membrane potential: Vmbecomes positive.

occurs when voltage gated Na+ channels on the excitable

membraneopen, allowing the flow of Na+into the cell

these channels are not the same as the Na+/K+pump thatgenerate the electrochemichal gradient

the AP is an all-or-none signal: its amplitude is invariable*

APs can only occur in excitable cells: neurons and muscle

cells

the repolarization of the membrane following an AP

depends on voltage-gated K+ channels

Ionic basis of the action potential


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Sequence of events:

at rest, all voltage-gated channels are closed

when Na+voltage-gated channels open: depolarization

(rising phase)

Na+channels then become inactive and K+voltage-gated

channels (not pictured) open: return(falling phase)after hyperpolarization, K+channels close and Na+channels

return to the closed conformation

Ionic basis of the action potential

Voltage gated Na+ channels & the action potential


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Voltage gated Na channels & the action potential

Changes in V and ionic conductances


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Vrest~ -70 mV

Rising phase:

Na+conductance (gNa) increases

Na+flows in(depolarization)

Falling phase:

gNadecreases

K+conductance (gK) increases

as the inwardNa+current decreases, an outwardflow of K+

occurs, resulting in hyperpolarizationAfter the AP:

gKdecreases

as the K+current decreases, the membrane returns to Vrest

Changes in Vmand ionic conductances

during an action potential

Changes in Vm and


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Changes in Vmand

ionic conductances during

an action potential

Ion cunductances (g)

Membrane polarity (V)

(not the direction of

ion currents)

Threshold potential


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The threshold potential is defined as the Vmat which an AP is

triggered 50% of the times.

Threshold potential

if a stimulating current is not intense enough to fire an AP

(1& 2,subthreshold stimuli), the resulting Vmis only

sustained for as long as the stimulus current is applied but

will return to Vrest

as soon as the stimulus ends

an AP response will continue without the stimulus current

overshoot: the period during which the membrane polarity is

reversed and the interior is more positive

membrane will quickly return directly to Vrest, or:it may go below Vrest: hyperpolarization (undershoot), then

slowly return to Vrest

a threshold current (3) triggers APs but can sometimes result

in a local response (an abortive AP)

The action potential is fired when the membrane reaches the


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e c o po e s ed w e e e b e e c es e

threshold potential in response to a stimulating current

The refractory periods after an action potential


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y p p

Immediately following an AP, a second AP is not possible

during the absolute refractory per iod(ARP).

the first stimulus current triggers an AP, buta second stimulus will not trigger an AP if applied within

the absolute refractory period

during the relative refractory period (RRP), an AP may be

triggered but only if the stimulus is more intense

the amplitude of any AP triggered during the relative

refractory period will be smaller

The refractory periods


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y p

after an action potential

Excitability of the

membrane:

zero during ARP

increases during RRP

(textbook toilet!)

The neuron threshold potential can increase in response


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p p

to slowly increasing subthreshold stimuli

Accommodation

Accommodation to sustained stimulation


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Phasic accommodation is a rapid accommodation to a

sustainedstimuluscurrent.

only 1-2 APs will occur, and only when the stimulus begins

Lowered accommodation response


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p

Tonic accommodation is slow accommodation.

APs will be fired repeatedly during stimulation, but with

decreasing frequency



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In thesomaand the dendrites,

a stimulus current elicited bya presynaptic cell induces a

voltage change (agraded

signal) that propagates until it

reaches thespike initiation

zone. If the current is still

strong enough when it reaches

the spike initiation zone, it willinduce APs (all-or- nothing

signals) that will propagate

down the axon.

signalswithinneurons

Propagation of the action potential


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p g p

The opening and closing of voltage-gated Na+channels

along the axon is sequential.

the current that flows through one Na+channel (or througha local group of Na+channels) provides the stimulus

(voltage change) to open the next channels

electrodes can measure membrane voltage at different

points along an axon

Propagation of the action potential


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p g p

Propagation of an action potential along an axon


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orange arrows: Na+

flowblue box: depolarized region

Propagation of an action potential along an axon


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orange arrows: Na+

flowblue box: depolarized region

The refractory periods after an action potential


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absolute: alllocal voltage-gated Na+channels are inactive

relative: local voltage-gated Na+channels are returning tothe closed conformation andsome voltage-gated K+

channels remain open

in an excitable membrane (a membrane that can elicit an

all-or-none response): all voltage-gated Na+and K+

channels are closed

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