Nerve and Muscle Physiology

In this topic we are going to cover

the following:

• the neuron –anatomy

• membrane potential, muscle,

• neuronal action potentials

 NEURON

 electrically excitable cell that processes & transmits

information through electrical & chemical signals

 functional unit of the nervous system

 maintain voltage gradients across their membranes

by means of metabolically driven ion pumps

 NEURON

 the ion pumps combine with ion channels embedded in

the membrane to generate intracellular & extracellular [

] differences of ions such as Na+, K+, C l-, & Ca2+

 neurons communicate by chemical & electrical

synapses in a process known as neurotransmission

(synaptic transmission)
NEURON: ANATOMY
SYNAPSES
SYNAPSE MAGNIFIED
 THE RESTING MEMBRANE POTENTIAL

 This is the voltage across the neural membrane at

rest

 It produces driving forces on the various ion

species such that they try to cross the neural

membrane.
 THE RESTING MEMBRANE POTENTIAL

 Due to electrochemical gradients, some cations try

to flow in whilst others try to flow out & some

anions try to flow in.

 At rest the membrane resists much of this ion flow

 THE RESTING MEMBRANE POTENTIAL
 Many ions have a [ ] gradient across the membrane.

 K+ ions : high [ ] intracellular; low [ ] extracellular

 Na+ & Cl- ions :high [ ] extracellular; low [ ] intracellular

 These [ ] gradients provide the potential energy to derive the formation

of the membrane potential

 The membrane potential is established when the membrane is

selectively permeable to one or more ions

 Ions diffuse down the [ ] gradient

 THE RESTING MEMBRANE POTENTIAL

 Under certain circumstances, the permeability of the

membrane can change dramatically for a short period of

time.

 This permits a selective but significant increase in ionic

flow across it

 Alters distribution of ions across the membrane

 Change in the voltage across the membrane

 As a result electrical signal is generated

 THE RESTING MEMBRANE POTENTIAL

At rest,

-the membrane is fairly permeable to K, thus

-its voltage potential (-70mV) is close to that of K (-90mV)

-K wants to flow out to bring the membrane potential to its

equilibrium potential.

 This creates a greater driving force for Na (Na wants to flow into

the neuron) whose equilibrium potential of +70mV is 140mV away.

 Cl wants to move into the neuron

THE RESTING MEMBRANE POTENTIAL
 ION PERMEABILITY OF THE MEMBRANE

 The lipid bilayer of neural membranes is impermeable to ions

 There are specialised protein complexes (ion channels),

commonly composed of 4-5 subunits surrounding a central

pore, within the membrane that allow ions to flow from one

side to the other

 Ion channel pores are usually selective for one or more types

of ions
 MECHANISMS RESPONSIBLE FOR GENERATION OF
THE RMP
 Na+/K+ ATPase
 Moves 3 Na+ ions out & moves 2 K+ ions in
 Results in the removal of one charge carrier from the
intracellular space
 Establishes the [ ] gradients of Na+ & K+ ions
 Selective permeability of the cell membrane for the
different ions
 Most cells have K+ selective ion channels that remain open
all the time
 Net efflux of K+ ions resulting in accumulation of xss
negative charge inside of the cell
 ION PERMEABILITY OF THE MEMBRANE

Ion channels in the membrane

 The variety of ion channels impart the functional

diversity on neurons

 Leakage channels appear to be always open within

normal range of physiological conditions

 Gated channels normally vary between opened & closed

states in response to extracellular or intracellular
conditions
 ION PERMEABILITY OF THE MEMBRANE

 Voltage-gated channels – the open or closed state is

determined by the voltage across the membrane. A

Subtype exists that responds immediately to voltage

changes & another that has a delayed response

(delayed rectifier)
 ION CHANNELS IN THE MEMBRANE

Chemical (ligand) –gated channels – the open or closed state

is determined by the binding of a ligand (neurotransmitter,

drug) to a specific site on the channel or by binding of

intracellular molecules (e.g. Phosphorus, Ca ions cAMP).

Different molecules can act on different subtypes of ion

channels facilitating permeability of the same ion

ION CHANNELS IN THE MEMBRANE
 Mechanically-gated channels – respond to stretch e.g. touch

receptors

 Some channels are both voltage & chemically gated

 Different ionic channels in neuronal membranes are

selective for K, Cl, Na & Ca (note : the significance of the

fact that ions tend to want to alter the membrane potential

to approach their own equilibrium potential

ION CHANNELS
 THE ACTION POTENTIAL (AP)

 The neuronal resting membrane potential is about -70mV

 An action potential occurs when a nerve is conducting a

nerve impulse.

 In order for an action potential to occur, the neuron must

receive sufficient stimulation to open enough Na ion

channels to reach the threshold level.

 THE ACTION POTENTIAL (AP)

 It is the signal that the nervous system uses to

transfer information over long distances.

 It occurs on the axon, produced by voltage-gated

channels on it.

 Because it must often travel a considerable distance,

it is periodically regenerated as it moves along.

 THE ACTION POTENTIAL (AP)
 If adequate Na ion channels are opened, to reach the threshold level
other Na & K ion channels will be stimulated to open
 Results in a self-propagating wave of action potential & Na & K ion
channels opening along the entire the length of the neuron

 Since an action potential will only occur when the membrane potential is
reached, an action potential can be described as an all or none response.

 An action potential can be divided into 2 phases: depolarization &

repolarization.
 ACTION POTENTIAL PHASES

 Resting potential – membrane is more permeable to K

(due to large numbers of K selective leakage channels)

than to Na (due to fewer numbers of Na selective leakage

channels) hence V is closer to K equilibrium potential (E )

K

 Depolarization – presynaptic input triggers an increase in

Na permeability due to opening of voltage-gated Na

channels (rapidly & spontaneously deactivating);

membrane potential then shifts to approach E .

Na
 ACTION POTENTIAL PHASES
• Repolarization

- Na conductance has gone back to the usual resting state due

to the inactivation of the voltage-gated Na channels.

- The membrane then becomes relatively more permeable to K

(the slower activating voltage-gated K channels are still

open, thus braking the rising/depolarization phase before it

reaches E ) initiating the membrane’s approach towards E

Na K.
 ACTION POTENTIAL PHASES
• Hyperpolarization – the membrane permeability to K
exceeds that at rest (due to opening of both the K
leakage channels & the voltage-gated K channels),
thus bringing membrane potential even closer to E . k

Over the course of this phase the permeability of K

shifts back (due to the closure of the voltage-gated K
channels) to what it was when the neuron was at rest
bringing the potential to the resting membrane potential
 PROPAGATION OF THE AP ALONG THE AXON

 The AP can be actively propagated because the membrane

contains voltage-gated ion channels that can be activated by

the spread of depolarisation resulting from the AP

 The +ve charges that are accumulating inside the axon

where the AP is taking place will be attracted toward the

next patch of membrane that is still at rest & where the

inside –ve relative to the outside

 PROPAGATION OF THE AP ALONG THE AXON

 As the +ve charges move toward that region at rest, they

depolarise the membrane enough to activate a significant number
of voltage-gated channels & an AP is now triggered at this next
patch of membrane
 This passive spread of the +ve charges is also called electrotonic
current spread, & represents active propagation of the AP
 The +ve charge is called electrotonic current
 Note – refractoriness of recently depolarised membrane (in
addition to hyperpolarisation of patches immediately adjacent to
that) prevent backflow of electrotonic current
 FACTORS AFFECTING AP CONDUCTION VELOCITY

 The conduction velocity of an AP potential determines

the speed of response to the stimuli initiating that AP

& this can mean the difference between life & death

 ↑axon diameter → ↓resistance to electrotonic current

→ ↑conduction of an AP in that axon

 ↓axon diameter → ↑resistance to electrotonic current

→ ↓conduction of an AP in that axon

FACTORS AFFECTING AP CONDUCTION VELOCITY

 Vertebrates have evolved myelination to effectively increase

conduction velocities; myelin sheaths
a)cover ion leakage channels – therefore increasing conduction
velocity by reducing current leakage;
b)reduce capacitance (ability to store charges & slow
conduction);
c)bring about saltatory conduction (whereby the AP seems to
leap from one node of Ranvier to another.
 Hence; a 12um diameter vertebrate axon can conduct an AP at
25m/sec
POSTSYNAPTIC POTENTIALS
 Postsynaptic potentials are usually much smaller changes in
membrane potential that occur on cell bodies & dendrites compared
to AP’s
 2 major classes of postsynaptic potentials:

i. Excitatory Postsynaptic Potentials (EPSPs)

ii. Inhibitory Postsynaptic Potentials (IPSPs)

 EPSPs- make the membrane potential more +ve than the resting
membrane potential
 IPSPs- make the membrane potential more –ve than the resting
membrane potential
 POSTSYNAPTIC POTENTIALS
 Postsynaptic potentials are not regenerated as they travel, thus

cannot travel long distances.

 Primarily produced by chemically gated ion channels in the

dendrites & cell body.

 Chemically gated ion channels are opened by neurotransmitters

released by the presynaptic neuron.

 Size & duration of postsynaptic potentials generated can be quite

variable, depending on the type & magnitude of presynaptic input

(bow & arrow)

 POSTSYNAPTIC POTENTIALS

 Postsynaptic potentials produced can add together to

produce larger changes in voltage, which if +ve enough,

would activate the voltage-ion gated channels on the

initial segment of the axon of the postsynaptic neuron.

 Initiation of an AP on the axon → travel of AP to axon

terminal.
POSTSYNAPTIC POTENTIALS
 TYPES OF SUMMATION

• Postsynaptic potentials can summate to produce larger

changes in postsynaptic membrane potentials.

• 2 types of summation:

i. Spatial summation

ii. Temporal summation

 REFRACTORY PERIOD

ABSOLUTE REFRACTORY PERIOD

 When the voltage-gated Na channels are inactivated
by depolarization phase, they can not be reopened
by depolarization of the membrane
 It’s virtually impossible to initiate another AP
 REFRACTORY PERIOD

RELATIVE REFRACTORY PERIOD

 A population of voltage-gated Na channels (in the

inactive state) undergoes a gradual transition back to the
closed state, in which the channels are now capable of
being reopened by a depolarization.

 As significant numbers of voltage-gated Na channels

return to the closed state, the axon again becomes
capable of initiating an AP.
 MAINTENANCE OF SIGNAL GENERATING CAPACITY

 A single AP has negligible effect on the ionic concentration gradients

across the plasma membrane though repeated AP’s would eventually
obliterate these gradients

 The Na-K-ATPase pump exports 3Na for every 2K imported into the
cell powered by ATP hydrolysis

 Note – the difference between a pump & an ion exchanger. Other

notable pumps are the Ca pump on the membrane of the ER &
mitochondria

 50% of the ATP consumed by the brain goes towards powering the Na-
K-ATPase pump
 CLINICAL CORRELATIONS

 ↑ K in the ECF → altered E (less –ve) → less –ve

K

V → smaller initial depolarization needed to reach

R

threshold for AP (increased excitability)

 Blockage of AP in sensory neurons from the

periphery by anaesthetic drugs, through the

blockage of the voltage-gated Na channels

 CLINICAL CORRELATIONS

 Hyperkalemic periodic paralysis (Quarter horses)

- characterised by episodes of paralysis/myotonia resulting

from genetic mutation of muscle voltage-gated Na channels

leaving them unable to close

 Continued inward leakage of Na → prolonged depolarization

→ inability to relax contracting muscle

 The high levels of Na in the cell strains the Na-K-ATPase

pump resulting in its failure to maintain the resting membrane

potential
 CLINICAL CORRELATIONS

Acute idiopathic polyradiculoneuritis (coon hound

paralysis)

- characterised by demyelination of the ventral roots & motor

nerves leading to weakness or paralysis & depression of

spinal reflexes.

 There is no treatment for the disease

 It runs its course in 3-6 weeks

COONHOUND
COONHOUND
 CLINICAL
CORRELATIONS
• Multiple sclerosis in humans

- characterised by an autoimmune attack on myelin

leaving behind hardened lesions of myelin (which

removes its ability to increase conduction velocities)

 INTRODUCTION TO SYNAPTIC TRANSMISSION

 Neuron functions as a communicator by passing information

about its activity to the next neuron

 A neuron can function as an integrator by receiving

multitudes of signals & then deciding whether to pass on a

signal to the next neuron or not

 Synaptic transmission enables both these abilities in

neurons
INTRODUCTION TO SYNAPTIC TRANSMISSION

 Animals & plants have evolved toxins that disrupt

synaptic transmission as a protective means
 Drug abuse is enabled through alteration of synaptic
transmission
 Pesticides (created by the humans) disrupt synaptic
transmission in pests but often human intoxication
occurs with accidental exposure to high
concentrations of these drugs
 SIGNIFICANCE OF CA & ITS MECHANISM OF
ENTRY

 Synaptic transmission is dependent on Ca influx at the axon

terminal through voltage-gated Ca channels on the axon

terminal plasma membrane

 The greater the magnitude of Ca influx, the greater the

magnitude of neurotransmitter release & the greater the

magnitude of post synaptic potentials

 This Ca influx is relatively insignificant on the membrane

potential
 ROLE OF CA IN THE STAGES OF VESICULAR
TRANSMITTER RELEASE
 At rest, synaptic vesicles are bound to cytoskeletal elements or to
each other by synapsin I (an integral vesicular membrane protein)
 Ca entering the cytosol binds to calmodulin (a cytosolic Ca-
sensing protein)
 The Ca-calmodulin complex then activates an enzyme that
modifies synapsin I causing detachment/mobilization of the
vesicles
 Synaptic vesicles can now approach the synaptic bouton
membrane
 ROLE OF CA IN THE STAGES OF VESICULAR
TRANSMITTER RELEASE
 Synaptobrevin (vesicle-associated membrane protein
[VAMP]) complexes with synaptosomal-associated protein
(SNAP-25 or syntaxin) on the bouton membrane.
 Results in docking (anchoring) of the vesicle to the internal
face of the bouton membrane. (This stage is Ca-independent)
 The membrane of the docked vesicle fuses with the bouton
membrane (fusion)
 Expulsion of the neurotransmitter into the synaptic cleft by
exocytosis (this stage is Ca-dependent)
 ROLE OF CA IN THE STAGES OF VESICULAR
TRANSMITTER RELEASE

 Synaptotagmin (another vesicular membrane protein) acts

as a Ca-sensor that plays a role in fusion & release since it

can bind both Ca & membrane phospholipid

 Synaptotagmin is also thought to act as a brake (during

rest) preventing fusion/release before activation of the axon

terminal.

 Ca influx & binding to synaptotagmin would remove this

brake to allow fusion/release to proceed

 SYNAPTIC TRANSMISSION

 There are 2 distinct pools of synaptic vesicles within the

neuron terminal:

i. bouton membrane & available for immediate release

upon activity-induced Ca influx

ii. reserve pool that is bound to the cytoskeleton & freed

for future release following an AP-induced Ca influx

 FATE OF THE STORAGE VESICLE AFTER
NEUROTRANSMITTER RELEASE

 The synaptic vesicle membrane is rapidly retrieved

from the synaptic bouton by endocytosis & can be

recycled for further transmitter release

 Retrieval involves elements of a pit-forming

mechanism capable of recognizing, coating & then

retrieving the incorporated vesicle membrane

 FATE OF THE STORAGE VESICLE AFTER
NEUROTRANSMITTER RELEASE

 Synaptotagmin plays an important role in the recognition of

the incorporated vesicle membrane

 Calcium plays a role in the final pinching-off of the coated pit

 Therefore; both synaptotagmin & Ca play a role in both

exocytosis & endocytosis/recycling of the synaptic vesicle

 Ultimately the recycled synaptic vesicle loses its coated pit

before rejoining the transmitter release process
SYNAPSE
 CLINICAL CORRELATIONS
 Black widow spider venom produces a spasmodic

hyperexcitability at the neuromuscular junction that is

followed by a subsequent failure of muscle activation

 Venom contains alpha-latrotoxin (a protein)

 Mechanism of intoxication: binds neurexin (on the synaptic

bouton membrane) to cause abnormal neurotransmitter

release ultimately leading to depletion of transmitter from

the terminal
 CLINICAL CORRELATIONS

• It is also speculated that this toxin induces formation

of a leakage channel that allows passage of Na, K &

Ca ions & may lead to a more +ve resting

membrane potential (hyperexcitability with

devastating end results)

BLACK WIDOW SPIDER
 CLINICAL CORRELATIONS

 Clostridial neurotoxins are proteases that prevent

neurotransmitter release through cleavage of

synaptobrevin (botulinum toxin), SNAP-25 or

syntaxin
 CLINICAL
CORRELATIONS
 Anatoxin-a (very fast death factor” )– cyanotoxin
produced by cyanobacteria found in algal bloom.
 The toxin binds the nicotinic Ach receptor
permanently causing a permanent contraction.
 Death results from dissociation of the brain &
musculature leading to suffocation
 CLINICAL CORRELATIONS
• Organophosphate poisoning

-OP inhibits acetylcholinesterase (AChE) thereby preventing

inactivation of Ach at the synaptic and neuromuscular junction.

-At the NMJ → weakness, fatigue, muscle cramps & paralysis.

-At the autonomic ganglia, → overstimulation of sympathetic

system (hypertension & hypoglycemia).

-In the CNS, → SLUDGEM (salivation, lacrimation, urination,

defaecation, GIT motility, Emesis & miosis.
 CLINICAL CORRELATIONS
 Lambert-Eaton myasthenic syndrome is an
autoimmune disorder in some cancer patients
characterised by muscle weakness & fatigue
 In this condition a reduction in Ach release at the
neuromuscular junction is a result of autoimmune
antibodies attacking both voltage-gated Ca (reducing
Ca influx) channels & synaptotagmin (thus impairing
exocytosis)