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Nerve and Muscle
Physiology of nerve
The neuron
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The basic structural unit of the nervous system.
Structure:
The soma
The dendrites: antenna like processes
The axon: hillock, terminal buttons
Types of nerve fibers
a- myelinated nerve fiber:
• Covered by myelin sheath, protein-lipid layer,
secreted by Schwann cells,
acts as insulator to ion flow,
interrupted at Nodes of Ranvier
b- unmyelinated nerve fiber:
• Less than 1μ, covered only with Schwann cells, as
postganglionic fibers
Electrical properties of a neuron
• Electrical properties of nerve & muscle are:
• 1-There is difference in electrical potential between
the inside and outside the membrane
• 2-Excitability: the ability to respond to any stimulus by
generating action potential
• 3-Conductivity: the ability to propagate action
potential from point of generation to resting point
Membrane potential; the basis of excitability
• Def: electrical difference between the inside & outside
the cell
• Causes: selective permeability of the membrane
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more K+, Mg2+, Ptn, PO4 inside
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more Na+, Cl-, HCO3-outside
• Exists in all living cells & it is the basis of excitability
• Excitability:
• Def: it is the ability to respond to stimuli (change in the
environment) giving a response
• The most excitable tissues are nerves & muscles
• Stimuli:
+anode
- cathode
• Types:
• Electrical (preferred), chemical, mechanical, or thermal.
• Cathode ( more important) & anode
Excitability
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Factors affecting effectiveness of the stimulus:
1- strength:
effective stimulus
2- duration:
a certain period of time, very short duration can not excite the
nerve
• 3- rate of rise of stimulus intensity:
• Rapid increase…. Active response
• Slow increase …. adaptation
Strength –Duration Curve
• Within limits stronger intensity shorter duration
• Strength:
• Threshold stimulus (rheobase): it is the minimal amplitude
of stimulus that can excite the nerve and produce action
potential.
• Subthreshold stimulus: causes local response
(electrotonic)
• Duration:
• stimuli of very short duration can not excite the nerve
• Utilization time: is the time needed by threshold stimulus
(Rheobase) to give a response
• :Chronaxie time needed by a stimulus double the
rheobase to excite the nerve, it is a measure of
excitability, decrease chronaxie means increase excitability
Stimulus amplitude
Strength –Duration Curve
chronaxi
e
2R
Utilization time
duration
R
Measuring the membrane potential
Recording:
by 2 micoelectrodes inserting
one inside the fiber & the
other on the surface &
connected to a voltmeter
through an amplifier
Types of membrane potential
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Membrane potential has many forms:
1- RMP
2- on stimulation;
a) action potential if threshold stimulus
b) localized response (electrotonic) if
subthreshold stimulus
Resting membrane potential
(RMP)
*definition: It is the difference in electrical potential
between the inside and outside the cell membrane
under resting conditions with the inside negative to the
outside
Recording: by 2
micoelectrodes inserting one
inside the fiber & the other on
the surface & connected to a
voltmeter
• Value:-90 mv large fibers, -70 in medium fibers, -20 in RBCs
• Causes
• 1- selective permeability
• 2- Na-K pump
Resting Membrane Potential
Selective permeability of the membrane: contributes to -86mv
 K+, ptn-, Mg2+&PO4- are concentrated inside the cell
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Na+, Cl-, HCO3- are found in the extracellular fluid
During rest the membrane is 100 times more permeable to K+ than to Na+,
K+tend to move outward through INWARD RECTFIER K+ channels down
their concentration gradient
The membrane is impermeable to intracellular Ptn-&other organic ions
Accumulation of +ve charges outside & -ve charges in
At equilibrium :K+ in to out is 35:1
Na+ in to out is 1-10
Potassium equilibrium
-90 mV
Na-K pump
• Definition: carrier protein on the
cell membrane:
• 3 binding sites inside for Na+
• 2 sites outside for K+
• 1 site for ATP
• Inner part has ATPase activity
• It is an electrogenic pump
Contributes for -4mv and helps
to keep RMP
• Nernest equation
• E for K = -61 log con inside/ conc outside
=- 94
• E for Na = -61 log con inside/ conc outside
=+ 61
• Goldman equation: it considers
• 1- Na, K and cl concentrations.
• 2- K permeability is 100 times as that for
Na
Action Potential
• Definition: It is the rapid change in
membrane potential following stimulation
of the nerve by a threshold stimulus.
• Recording: microelectrodes and
oscilloscope.
Membrane Permeabilites
• AP is produced by
an increase in Na+
permeability.
• After short delay,
increase in K+
permeability.
Figure 7-14
Shape and Phases of Action
Potential
• 1- Stimulus artifact.: small deflection indicates the time of application
of stimulus, it is due to leakage of current
• 2- Latent Period: isoelectrical interval, time for AP to travel from site
of stimulation to recording electrode.
• 3- Ascending limb (depolarization):starts slowly from -90, till firing
level-65mv, reaches &overshoots the isopotential, ends at +35
• 4- Descending limb:(repolarization):
starts rapidly till 70% complete then slows down
* Hyperpolarization: in the opposite direction
slight & prolonged
• 5- RMP
Shape and Phases of Action
Potential
+35
overshoot
0
depolarization
repolarization
mv
1- Ascending limb
(depolarization)
Slow..firing level..rapid.
2- Descending limb
(repolarization)
rapid then slow
3- Hyperpolarization:
slight & prolonged
4- RMP
-65
FL
hyperpolarization
-90
Latent period
time
Duration of Action Potential
• Spike lasts 2msec
• Hyperpolarization 35-40msec
Ionic basis of action potential
• Depolarization is caused by Na+ inflow
• Repolarization is caused by K+ outflow
Two types of gates:
1- voltage gated Na+ channels; having 2 gates: outer activation gate & inner
inactivation gate
2- voltage gated K+ channels; one activation gate
When the nerve is stimulated::
a- the outer gate of VG Na+ opens, activating Na+ channel…. Na+ inflow
b- the inner gate of Na+ channels closes, inactivating Na+ channels… stop Na
inflow
c- K+ gates open, activating K+ channels, K+ outflow
The Action Potential
A stimulus opens activation gate of some
Na+ channels depolarizing membrane
potential, allowing some Na to enter,
causing further depolariztion
If threshold potential is reached, all Na+
channels open, triggering an action
potential.
The Action Potential
1-Depolariztaion:occurs in 2 stages:
Slow stage: -90 to -65mv: some Na+
channels opened, depolarizing
membrane potential, allowing some
Na to enter, causing further
depolarization
At -65mv, the firing level or
threshold for stimulation, all Na+
channels open, triggering an action
potential.
Rapid stage: -65 to +35: all Na+
channels are opened, Na+ rush into
the fiber, causing rapid depolarization
The Action Potential
Within a fraction of msec, Na+
channel inactivation gates close
and remained in the closed state
for few milliseconds, before
returning to the resting state.
2- Repolarization: Inactivation
of Na+ channels and activation of
K+ channels are fully open.
Efflux of K+ from the cell drops
membrane potential back to and
below resting potential
3- Hyperpolarization; slow
closure of K+ channels
The Action Potential
The Na+ & K+ gradients after action potential are
re-established by Na+/K+ pump
Only very minute fraction of Na+ & K+ share in
action potential from the total concentration
The action potential is an all-or-none response.
(provided that all conditions are constant, AP once
produced, is of maximum amplitude, constant duration
& form, regardless the amplitude of the stimulus ,
however threshold or above
Action potential will not occur unless depolarization
reaches the FL (none)
Action potential size is independent of the stimulus
and once depolarization reaches FL, maximum
response is produced, reaches a value of about +35
mV(all)
The Action Potential
Both gates of Na+
channel are
closed but K+
channels are still
open.
K+ channels finally close and Na+ channel
inactivation gates open to return to resting state.
Continued efflux of K+ keeps
potential below resting level.
Action potential initiation
S.I.Z.
Action potential termination
Action potential in a nerve trunk
• Nerve trunk is made of many nerve fibers
• The AP recorded is compound action
potential, having many peaks
• The individual fibers vary in:
• 1- threshold of stimulation
• 2-distance from stimulating electrode
• 3- speed of conduction
• During depolarization, there is +ve feed back response.
• Repolarization is due to:
1- inactivation of Na+ channels( must be removed before another AP
2- slower & more prolonged activation of K+ channels
• Hyperpolarization (undershoot): slow closing of K+ channels, K+
conductance is more than in resting states
• Role of Inward rectifier K+ channels:
Non gated channels
Tend to drive the membrane to the RMP
Drive K+ inwards only in hyperpolarization
Re-establishing Na+ &K+ gradient after AP:role of Na+ /K+ pump
All or none law
Electrotonic potentials & local response
• Catelectronus: at cathode/ depolarization less than 7mV/ passive
• Anelectronus: at anode/ hyperpolarization/ passive
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Local response (local excitatory state):
Stonger cathodal stimuli
Slight active response
Some Na+ channels open, not enough to reach FL
It is graded
Does not obey all or none law
Non propagated
Excitability of the nerve increased
Caused by subthreshold stimulus
Can be summated & produce AP
Has no refractory period
Local Response (local excitatory change)
• Although subthreshold stimuli do not
produce AP they produce slight active
changes in the membrane that DO NOT
PROPAGATE.
• It is a state of slight depolarization caused
by subthreshold cathodal stimulus that
opens a few Na channels not enough to
produce AP
Local Response (local excitatory change)
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It differs from AP :
It does not obey all or non rule
Can be graded.
Can be summated.
It does not propagate.
Excitability changes during the action potential
• Up to FL, excitability increases
The remaining part of action potential, the
nerve is refractory to stimulation (difficult to
be restimulated)
• Absolute refractory period:
Def: the period during which a 2nd AP can
not be produced whatever the strength
of the stimulus
Length: from FL to early part of
repolarization
Causes: inactivation of Na+ channels
• Relative refractory period:
Def.; the period during which membrane
can produce another action potential,
but requires stronger stimulus.
Length: from after the ARP to the end of
the AP
Causes: some Na+ channels are still
inactivated
K+ channels are wide open.
ARP
FL
Increased
excitability
RRP
Factors affecting Membane potential & Excitability
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Factors ↑ excitability:
* Role of Na+
1) ↑ Na permeability (veratrine & low Ca 2+).
Factors ↓ excitability:
1)↓ Na permeability( local anaesthesia & high Ca2+) [ membrane
stbilizers]
Decrease Na+ in ECF: decreases size of AP, not affecting RMP
Blockade of Na+ channels by tetradotoxin TTX decrease excitability
& no AP
** Role of K+:
1)↑ K extracellularly (hyperkalemia).
2)↓ K extracellularly (hypokalemia): familial periodic paralysis
3) blockade of K+ channels by TEA: prolonged repolarization& absent
hyperpolarization
*** Role of Na+ K+ pump: only prolonged blockade can affect RMP &
AP
Accommodation of nerve fiber
• Slow increase in the stimulus intensity
gives no response:
• 1- inactivation of Na+ Channels
• 2- opening of K+ Channels
Conduction in an Unmyelinated Axon
• The action potential generated at
one site, acts as a stimulus on
the adjacent regions
• During reversal of polarity, the
stimulated area acts as a current
sink for the adjacent area
• A local circuit of current flow
occurs between depolarized
segment & resting segments
(flow of +ve charges) in a
complete loop of current flow
• The adjacent segments become
depolarized, FL is reached, AP is
generated
Figure 7-18
Conduction in Myelinated Axon
(Saltatory conduction)
• Myelin prevents movement of
Na+ and K+ through the
membrane.
• The conduction is the same in
unmyelinated nerve fibers
Except that AP is generated
only at Nodes of Ranvier
• AP occurs only at the nodes.
– AP at 1 node depolarizes
membrane to reach threshold
at next node.
• The +ve charges jump from
resting Node to the the
neighbouring activated one
(Saltatory conduction).
Figure 7-19
Importance of saltatory conduction:
• ↑velocity of nerve conduction.
• Conserve energy for the axon.
Orthodromic & antidromic conduction
• Orthodromic: from axon to its termination
• Antidromic: in the opposite direction
• Any antidromic impulse produced, it fails
to pass the 1st synapse & die out
Monophasic &biphasic AP
• Monophasic AP: recorded by one
microelectrode inserted inside the fiber &
one indifferent microelectrode on the
surface.
• Biphasic: two recording electrodes on the
outer connected to CRO
Depolarization & repolarization of a nerve fiber
• RMP does not record any
change
• Depolarization flows to the +ve
electrode ..... Upright deflection
(+ve wave)
• Complete depolarization ... No
flow of current (baseline)
• Repolarization to the +ve
electrode....down deflection
• Complete repolarization ... No
flow of current (baseline)
Action potential in a nerve trunk
• Nerve trunk is made of many nerve fibers
• The AP recorded is compound action
potential, having many peaks
• The individual fibers vary in:
• 1- threshold of stimulation
• 2-distance from stimulating electrode
• 3- speed of conduction
Compound AP
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Graded
Subthreshold; no response occurs
Threshold; a small AP, few nerve fibers
Further increasing; AP amplitude
increases up to a maximal
• Increasing the intensity, supramaximal
stimuli, no more increase in the AP
Nerve fiber types
• According to their thickness, they are divided into:
diameter
conduction
Spike
duration
Remarks
A fibers
2-20 micron
20-120m/s
0.5 msec
Alpha, beta, gamma & delta
Most sensitive to pressure
B fibers
1-5 micron
5-15m/s
1msec
Preganglionic autonomic f
Most sensitive to hypoxia
C fibers
<1 micron
0.5-2m/s
2msec
Postganglionic autonomic f
Most sensitive to local
anesthetics
Metabolism of the nerve
• Rest: nerve needs energy to maintain polarization of the
membrane, energy needed for Na+/K+ pump, derived
from ATP. Resting heat
• Activity: pump activity increases to the 3rd power of Na+
concentration inside, if Na+ concentration is doubled, the
pump activity increases 8 folds;23 .
• Heat production increases:
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1- initial heat during AP
2- a recovery heat, follows activity =30 times the initial heat
• Neurotrophins:
• Proteins necessary for neuronal development, growth & survival
• Secreted by glial cells, muscles or other structures that neuron
innervate
• Internalised & retrograde transported to the cell body
Types of muscles
• Skeletal muscle: under voluntary control 40% of total body mass.
• Cardiac muscle: not under voluntary control.
• Smooth muscle: not under voluntary control. Both are 10% of total
body mass
Skeletal muscles
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Attached to bones
>400 voluntary skeletal muscles
Contraction depends on their nerve supply
4 functions:
1- force for locomotion & breathing
2- force for maintaining posture & stabilizing joints
3- heat production
4- help venous return
Morphology
• Muscle fibers:
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Bundled together by C.T.
Arranged in parallel between 2 tendenious ends
Is a single cell
Closely enveloped by glycoprotein sheath (sarcolemma)
outside the cell membrane
• Made of many parallel myofibrils embeded in a
sarcoplasm, between a complex tubular system
Skeletal muscle
• Each muscle fiber is a single unit. It is made up of many
parallel myofibrils embedded together and a complex
sarcotubular system.
• Each muscle fibril contains interdigitating thick and thin
myofilaments arranged in sarcomeres.
• 2 major proteins:
• 1- thick filaments [myosin]
• 2- thin filaments [actin, troponin, troopomyosin]
• Troponin & trpomyosin regulate muscle contraction by
controlling the interaction of actin & myosin
The sarcomere
• It is the functional unit of the
muscle.
• It ext\ends between two
sheets called Z lines.
• Thick filaments (Myosin) in
the middle (dark band (A)).
• Thin filaments on both sides
(light band (I) ).
• Z line in the middle of I band.
• H zone in the middle of A
band.
• When the muscle is
stretched or shortened, the
thick & thin filaments slide
past each other, and the I
band increases or decreases
in size
Internal organization:
Striations:
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Myofilaments
1- thick filaments (myosin):
300 myosin molecules
2 heavy chains & 4 light chains
Each myosin molecule has two heads
attached to a double chains forming helix
tail.
myosin head contain actin – binding site,
an ATP- binding site and a catalytic site
(ATPase).
Each myosin head protrude out of the thick
filaments forming cross bridges that can
make contact with the actin molecule
2- Thin filaments (actin)
Actin, tropomyosin, troponin.
Actin is a double helix that has active
sites for combines with myosin cross
bridges.
Troponin: 3 subunits I for Actin binding, T
for tropomyosin binding, C for Ca binding.
Sarcotubular system
• Consists of T-tubules and Sarcoplasmic reticulum.
• T tubules consists of network of transverse tubules surround
each myofibril, at the junction of the dark and light bands.
• T tubules are invaginations from cell membrane.
• T tubules contain extracellular fluid.r
• T tubules transmit the AP from the surface to the depth of the
muscle fiber.
• Sarcoplasmic reticulum: surrounds each myofibril, run parallel to it
• Sarcoplasmic reticulum: extends between the T tubules.
• Sarcoplasmic reticulum: are the sites for Ca storage.
• Sarcoplasmic reticulum ends expands to form terminal cistern,
which makes specialized contact with the T tubules on either side
• Foot processes span the 200 A0 between the 2 tubules
• SR contains protein receptor called Ryanodine that contains the
foot process and Ca channel
• T tubule contains voltage- senstive dihydropyridine receptor that
opens the ryanodine channel
The muscle protein
• Myosin protein:
• Thick filaments: 300 myosin molecules
• Myosin molecule is made up of 2 heavy chains coil around
each other to form a helix.
• Part of the heliix extends to side to form an arm
• Terminal part of the helix with 4 light chains combine to form 2
globular heads
• The arm & head are called cross bridges, flexible at 2 hinges,
one at the junction between the arm leaves the body, the 2nd
at the attachment of the head with the arm
• The myosin heads contain an actin –binding site, catalytic site
for hydrolysis of ATP
Myosin thick filaments
Thin filaments
Backbone is formed of 2 chains of actin,
forming helix, has active site, 300-400
molecules
Tropomyosin: long filaments, located in the
groove between the 2 chains of actin, covers
the active sites, 40-60 molecules.
Troponin: small, globular, formed of 3 parts;
1-TI
2-TT
3- TC
Actin
tropomyosin
Ca2+
• α actinin binds actin to the Z line
Neuromuscular Junction
• Def: it is the area lies between the nerve ending of the alpha motor neurons and skeletal
muscle.
•Structure of the NMJ :
•1) terminal knobs
2)Motor End Plate (MEP)
•contain Ach vesicle
contain Ach receptors
3)Synaptic cleft
contain choline estrase
• Steps Of Neuromuscular Transmission:
•1) Arrival of action potential : ↑ permeability to Ca2+ .. Rupture of vesicles.
•2) Postsynaptic response: ↑ conductance to Na and K more Na influx…end plate potential
•3) EPP: graded, non propagated response that act as a stimulus that depolarizes the adjacent
membrane to firing level… AP…. Muscle contraction.
•4) Acetyl choline degradation
end plate
Neuromuscular junction
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Properties of neuromuscular transmission:
1) unidirectional: from nerve to muscle
2) delay: 0.5msec
3) fatigue: exhaustion of Ach vesicles.
4) Effect of ions: ↑Ca….. ↑ release of Ach
↑ Mg….↓ release of Ach
5) Effect of drugs:
* Drugs stimulate NMJ
• Ach like action Metacholine, carbachol, nicotine small dose.
• inactivating choline esterase neostigmine, physostigmine,
diisopropyl phlorophosphate.
* Drugs block NMJ: curare competes with Ach for its
receptors
Motor end plate is a highly specialized region of the muscle plasma membrane.
Myasthenia Gravis (MG)
 Serious may be fatal disease of neuromuscular junction
 Characterized by weakness of skeletal muscle, easy
fatigability may affect the respiratory muscles and cause death
 More in female
 It is suspected to be a type of autoimmunity (the patient
antibodies attack the acetyl choline receptors at the
neuromuscular junction)
 Treatment:
 Adminestration of drugs as neostigmine, inactivating
acetylcholinesterase
Changes that occurs in the skeletal
muscle after its stimulation
1- electrical changes: action potential
2- Excitability changes: ends before the
beginning of contraction
3- chemical changes: at rest & during
activity
4- mechanical changes: contraction
Electrical changes
Nerve action potential
Muscle action potential
RMP
-70mV
-90mV
Rate of conduction
According to myelination
5m/sec
duration
shorter
longer
After AP
Release of acetyl choline Contraction after 2msec
+35
-70
+35
-90
Excitability changes
• It is like changes that occurs in the nerve during action potential (increased
excitability, ARP, RRP, Supernormal excitability, subnormal excitability,
normal)
• The refractory period ends at the time of beginning of contraction, so during
contraction, the excitability is normal, can respond to another stimuli
Mechanical changes
AP
Electrical changes in the muscle
• Similar to nerve action potential:
• RMP: -90mv
• AP lasts 2-4msec &precedes muscle
contraction by 2msec
• Single muscle fiber obeys all or none rule
Muscle Twitch
a single action potential causes a brief contraction followed by
relaxation
The twitch starts 2msec after the start of depolarization, before
the repolarization is complete
Excitability changes
• It is like changes that occurs in the nerve (refractory) during action potential
• The refractory period ends at the time of beginning of contraction, so during
contraction, the excitability is normal, can respond to another stimuli
Mechanical changes
AP
Mechanical changes [excitation-contraction coupling]
Action potential produce muscle contraction in 4 steps;
• 1- release of Ca2+: AP pass through T tubules,
causing Ca release from the terminal cistern into the
cytoplasm
• 2- activation of muscle proteins: Ca2+ binds
troponin, moves tropomyosin away from active site of
actin, actin binds with myosin, contraction starts
• 3- generation of tension: binding, bending,
detachment, return
• 4- relaxation: active process, when Ca is removed
frrom the cytoplasm & actively pumped into the SR
Action Potentials and Muscle
Contraction
Mechanism of muscle
contraction
Cross-bridge formation:
Types of Muscle Contractions
• Isotonic: Change in length
(muscle shortens) but
tension constant
• Isometric: No change in
length but tension
increases e.g. Postural
muscles of body
• Muscle contraction in the body is
a mixture of both types e.g.
when person lifts a heavy object,
the biceps starts isometric, then
isotonic contraction
Factors affecting muscle contraction
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1- type of muscle fiber:
Slow red fiber: Slow contraction & relaxation, rich in myoglobin, not easily fatigued,
adapted for prolonged weight bearing, e.g. soleus muscle
Rapid pale fiber: rapid contraction & relaxation, poor myoglobin, easily fatigued,
adapted for skilled movements, e.g. hands & extraocular muscles
2- type of load:
Preload: load applied to the muscle before contraction changing its initial length,
[within limits, the more the initial length, the more the tension in isometric contraction]
Afterload: load added to the muscle after it starts contraction [the more the after
load, the less will be the velocity of contraction
3- stimulus factor:
Stimulus strength: the more strength of the stimulus, the more the fibers stimulated,
the more force of contraction
Stimulus frequency:
low frequency; separate twitches
Medium frequency; clonus
High frequency; tetanus
4- fatigue: repeated stimulation of the muscle results in fatigue due to:
Depletion of ATP,CP & glycogen consumption of acetyl choline
Accumulation of metabolites decreased O2 & nutrient supply