2. 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
3. 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)
7. 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.
8. 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
9. 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
10. 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
An electrical signal is generated
11. 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
13. 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
14. 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
15. 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)
16. 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
17. 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
19. 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.
20. 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.
21. 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.
22.
23. 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 (EK)
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 ENa.
24. 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 ENa) initiating the membrane’s approach towards EK.
25. 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 Ek.
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
26.
27. 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
28. 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
29. 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
30. 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 & therefore
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
31.
32.
33. 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
34. 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)
35. 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.
37. 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
38.
39.
40. REFRACTORY PERIOD
ABSOLUTE REFRACTORY PERIOD
When the voltage-gated Na are inactivated by
depolarization phase, they can not be reopened by
depolarization of the membrane
It’s virtually impossible to initiate another AP
41. 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.
42. 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
43.
44. CLINICAL CORRELATIONS
↑ K in the ECF → altered EK (less –ve) → less –ve
VR → smaller initial depolarization needed to reach
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
45. 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
46. 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 disease
It runs its course in 3-6 weeks
49. 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)
50. INTRODUCTION TO SYNAPTIC TRANSMISSION
Neuron functions as a communicator by passing
information about it 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
51. 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
52. 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
53. 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
54. 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)
55. 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
56.
57. 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
58. 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
59. 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
61. 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
62. 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)
64. CLINICAL CORRELATIONS
Clostridial neurotoxins are proteases that prevent
neurotransmitter release through cleavage of
synaptobrevin (botulinum toxin), SNAP-25 or
syntaxin
65. 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
66. 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.
67. 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)
78. INTRODUCTION TO MUSCLE PHYSIOLOGY
Running, jumping, swimming, flying, climbing, digging,
respiration, digestion, swallowing, parturition, moving blood &
lymph, glandular secretion, eye movement, vocalization all rely
on muscle tissue as the ‘engine’ of performance
Muscle can perform these by being contractile, whereupon they
pull on other structures
Muscle is highly adaptable; can change the size and/or number
to meet its environmental demands
Skeletal, cardiac & smooth muscle varieties
79. INTRODUCTION TO MUSCLE PHYSIOLOGY
Physiological properties of muscle
Contractility – ability to shorten
Excitability – ability to receive & respond to stimuli
Extensibility – ability to be stretched
Elasticity – ability to return to its original shape
after contraction or being stretched
Ability to produce movement – related to all of the
above properties
80. INTRODUCTION TO MUSCLE PHYSIOLOGY
Muscle also functions in generation of heat (shivering)
or as a source of nutrition (during starvation)
Maximum contractile force of a muscle is proportional
to its cross sectional area
Morphological & physiological cross sections are
identical in parallel muscles but the physiological cross
sectional area is larger than the morphological cross
sectional area
84. TYPES OF MUSCLE FIBRES
• Slow-twitch /type I/red muscle fibres
- produce low amounts of force, contract slowly, but have a
high capacity for oxidative phosphorylation.
- Ideal for high levels of endurance e.g. during migrations
• Fast-twitch/type II/white muscle fibres
- produce high amounts of force, contract very quickly, & have
a capacity for anaerobic glycolysis.
- ideal for fast movements during predator evasion
85. TYPES OF MUSCLE FIBRES
Type IIa – have greater oxidative capacity
Type IIb – produce the highest amount of force. Absent in canines
Tonic fibres – found in neuromuscular spindles & extraocular
muscles of mammals & in postural muscles of amphibians, reptiles
& birds. These contract at very slow frequency rates (in
comparison to twitch fibres) but not as easily fatigued
Reasons for differences
- slower contractile protein interaction & differences in innervation
(multiple synapses along the fibre in contrast to single synapse at
mid-point of fibre)
86. SUBCELLULAR ORGANISATION OF SKELETAL
MUSCLE
Muscle fibre = muscle cell = myocytes = 5 to 100um in
diameter = half a million sarcomeres
Fusion of myoblasts (immature cells) occurs during
development resulting in myocytes containing multiple nuclei
located just below the plasma membrane
Myofibrils (1-2um in diameter) occupy 80% of the myocyte =
contractile elements (other physiologist argue that the
sarcomere is the contractile element) = thousands of
sarcomeres
87.
88. Thin (actin) filaments extend in both directions from the Z
lines (or Z disks)
Thick (myosin) filaments extend in both directions from the
M (mitte) lines (containing energy-metabolizing enzymes eg
creatinine phosphokinase)
The A (anisotropic) band appears dark due to the overlap (6
thin filaments surround 1 thick filament) of the thin & the
thick filaments (there are only thick filaments)
SUBCELLULAR ORGANISATION OF SKELETAL
MUSCLE
89. SUBCELLULAR ORGANISATION OF SKELETAL
MUSCLE
The H (helle) zone is found at the centre of the A band & is a
lighter area within the A band due to lack of overlap of thin &
thick filaments
The I (isotropic) band is made up by the lighter regions of
adjacent sarcomeres (demarcated by the Z line) = thin
filaments which are not in overlap with thick filaments
Myosin heads (with the ability to hydrolyse ATP)project from
the thick filaments & make contact (through cross-bridges)
with the actin filaments during contraction
90.
91.
92.
93.
94. THE SARCOPLASMIC RETICULUM
The sarcoplasmic reticulum (SR) though specialized
corresponds to the smooth endoplasmic reticulum
It is in close association with the inner aspect of the plasma
membrane
It is an important storage site for calcium & hence is
important in initiation & termination of muscle contraction
It has an anastomosing, channel-like structure that surrounds
each myofibril
95. THE SARCOPLASMIC RETICULUM
Inward extensions of the plasma membrane
(transverse [T] tubules) are closely associated with
the SR = communication link between cell
membrane & myofibrils
In mammals there are two T-tubules, one over each
A & I band junction where it confluents with a
dilation, the terminal cisternae
96. THE SARCOPLASMIC RETICULUM
The triads are the associations of the T-tubules &
the SR
Electrical excitation of the plasma membrane →
excitation of the T-tubule → excitation of SR →
release of Ca into cytosol of muscle cell →
contraction (within milliseconds allowing all
myofibrils to contract at the same moment)
97.
98.
99. THE SLIDING FILAMENT THEORY
Sarcomeres (and thus myofibrils) shorten because
actin filaments slide over myosin filaments.
The actin are actually pulled in toward the M line in
a ratchet like fashion by myosin (by repetitive
attachment & release by myosin heads)
As the actin filaments are pulled closer to the centre
of the sarcomere, the sarcomere shortens because
the actin filaments are anchored in the Z lines
100. THE SLIDING FILAMENT THEORY
The sliding filament model of muscle contraction
states that during contraction, the thin filaments
slide past the thick filaments.
The thick filaments pull the thin filaments toward
the center of the sarcomere.
101. THE SLIDING FILAMENT THEORY
Overlap between the myofilaments increases as the thin
filaments slide they pull the Z discs toward each other
and the sarcomere shortens.
All of the sarcomeres along the myofibril shorten (and
all of the myofibrils within the muscle fiber shorten)
which causes the entire muscle to shorten - this is
muscle contraction.
102. THE MOLECULAR BASIS OF CONTRACTION
Actin can be globular (G actin) [42kD]in solution or
polymerized fibrous (F actin) in whole muscle
Actin stimulates myosin’s ability to hydrolyse ATP
There are about 500 myosin heads on each thick
filament but they have opposite polarity on different
sides of the M line
103. THE MOLECULAR BASIS OF CONTRACTION
This ensures that actin filaments on either side of the M
line are pulled toward the middle of the sarcomere
during repetitive cycling [5 cycles/sec]of cross-bridge
formation.
Myosin heads are not all attached to an actin filament
simultaneously
This allows for a continuous pull on the actin filaments
during contraction (smooth Vs rigid sliding)
104. THE MOLECULAR BASIS OF CONTRACTION
Myosin is a larger (520kD) protein with a double-
headed globular region joined to a long tail (or rod-like
structure) = an ATP hydrolysing enzyme (5 to 10
molecules per second)
Light meromyosin (LMM) – tail (responsible for
spontaneous assembly into thick filaments)
Heavy meromyosin (HMM) – globular head
(responsible for the actin binding associated with the
cross-bridge formation) & neck region
105.
106. PROPOSED SEQUENCE OF EVENTS OF A CROSS-
BRIDGE CYCLE
A myosin head binds to an ATP molecule forming a complex
Myosin-ATP complex then binds to F-actin
Hydrolysis of the ATP molecule then occurs, providing energy
for turning myosin head about its hinge & creating a pulling
force on the actin
In order for the myosin head to detach, it must bind a new
ATP molecule
The new myosin ATP complex binds to another F-actin & the
cycle repeats itself
In death, rigor mortis occurs, because when muscle cells
die, ATP is depleted, & therefore cross-bridges cannot be
detached from the actin
107.
108.
109.
110. SMOOTH MUSCLE CELLS
Small, spindle-shaped cells with one central nucleus, and
Lack the coarse connective tissue coverings of skeletal
muscle.
Usually arranged into sheets of opposing fibres, forming a
longitudinal layer and a circular layer.
Contraction of the opposing layers of muscle leads to a
rhythmic form of contraction, called peristalsis, which propels
substances through the organs.
111. SMOOTH MUSCLE
Smooth muscle lacks neuromuscular junctions,
but have varicosities
Varicosities- numerous bulbous swellings that
release neurotransmitters to a wide synaptic cleft.
113. SMOOTH MUSCLE
No striations & no sarcomeres
Lower ratio of thick to thin filaments when
compared to skeletal muscle
But thick filaments have myosin heads along their
entire length.
Smooth muscle has tropomyosin but no troponin;
calmodulin binds calcium
114. SMOOTH MUSCLE
In smooth muscle thick and thin filaments are arranged
diagonally, spiral down the length of the cell, and
contract in a twisting fashion.
Smooth muscle fibers contain longitudinal bundles of
noncontractile intermediate filaments anchored to the
sarcolemma and surounding tissues via dense bodies
118. TYPES OF SMOOTH MUSCLE
Types of Smooth Muscle
Single-unit (unitary) smooth muscle
a.k.a. visceral muscle, is the
Most common type of smooth muscle.
It contracts rhythmically as a unit
Electrically coupled by gap junctions
Exhibits spontaneous action potentials.
119. TYPES OF SMOOTH MUSCLE
Multiunit smooth muscle
-Located in large airways to the lungs, large arteries,
erector pili muscles in hair follicles, and the iris of the
eye.
- It consists of cells that are structurally independent of
each other,
-Possess motor units
-Capable of graded contractions
121. SMOOTH MUSCLE CONTRACTION
Ca2+ - activated phosphorylation of myosin rather
than Ca2+ binding to troponin complex initiates
muscle contraction
Termination of crossbridge cycling occurs when the
myosin light chain phosphatase removes the
phosphate groups from the myosin heads
123. CALCIUM-REGULATED CONTROL
Troponin & tropomyosin are specialized accessory
proteins associated with actin filaments = 30% of thin
filaments
In resting muscle, tropomyosin (rod-shaped) sits in a
groove (of an actin filament) blocking the interaction of
myosin heads with actin
Tropomyosin is also thought to stabilize the structure of
actin
124. CALCIUM-REGULATED CONTROL
Troponin is a complex of 3 troponins (C [calcium-
binding], T [tropomyosin-binding], & I
[inhibitory])
C & I form a globular head region whilst T forms a
long tail-like structure
C structure resembles that of calmodulin (calcium
sensor found in many cells types)
125.
126. CALCIUM-REGULATED CONTROL
• When a skeletal muscle is stimulated to contract by
its motor nerve, the signal is an action potential (AP)
that spreads over a muscle cell plasma membrane.
• The AP sweeps down into the T tubules & thus deep
into the muscle cell, stimulating the SR to release its
stored Ca ions through its large Ca release channels
127. CALCIUM-REGULATED CONTROL
A model suggests that when the T tubule depolarizes,
voltage-sensitive dihydropyridine receptors undergo a
conformational change which dislodges the ryanodine
receptors from Ca channels in the SR (pulling the plug)
The Ca ions diffuse into the cytosol & bind to troponin
C (each troponin C can bind up to 4 Ca ions) causing a
conformational change in troponin C resulting in the
movement of tropomyosin thereby exposing the myosin
binding sites on actin → myosin & actin binding
128. ENERGETICS OF CONTRACTION
Chemical energy → mechanical energy for muscle contraction
Muscles waste only 30-50% (compared to the 80% for petrol
engines) of the energy as heat
The hydrolysis of ATP provides the chemical energy for
muscle contraction
ATP has a high turnover; most cells consume an ATP molecule
within 1 min of its formation, therefore there is need for its
continuous production
If a muscle cannot maintain its supply of ATP, it will go into
rigor mortis
129. ENERGETICS OF CONTRACTION
During prolonged endurance exercise, fatty acids are aerobically
metabolized (Beta-oxidation) to acetyl CoA then through the citric
acid cycle to then yield ATP
ATP is also needed to pump Ca ions (by plasma membrane Ca
ATPase pumps) used during excitation-contraction coupling back
into the SR (25 -30%)
Inside the SR, Ca is bound to calsequestrin & thus free Ca ions in
the SR is low
An energy dependent mechanism is necessary for the return of Ca
ions from the cytosol after muscle contraction
130. NEUROMUSCULAR FUNCTION
A motor unit consists of one motor neuron & all the skeletal
muscle fibres it innervates.
A whole skeletal muscle is composed of many motor units
Therefore its force of contraction is varied by the way of the
control of the CNS in stimulating the appropriate number of
motor units
Largest motor units - in the limbs & postural muscles &
smallest motor units are found in association with eye
movements
131. NEUROMUSCULAR FUNCTION
The localized region of communication between an axon & a
muscle fibre is called a neuromuscular junction (motor end
plate or motor terminal)
Occurs at the mid-point of a muscle fibre
Axon is separated from the end plate by a 50nm synaptic
cleft
Acetylcholine is the neurotransmitter stored in synaptic
vesicles (up to 100 000) of the axon terminal of the motor
neuron
132. NEUROMUSCULAR FUNCTION
Arrival of an AP at the axon terminal triggers release of Ach
by exocytosis into the synaptic cleft
Binding of Ach to post synaptic receptor sites stimulates an
electrical change in the post synaptic cell membrane, which
leads to muscle contraction
The Ach receptor is a ligand-gated ion channel (pentameric
membrane protein) whose conformation changes to an open
state (lasting about 1 msec) upon binding Ach
The alpha subunit is the one that binds Ach
136. SIGNAL FOR RELEASE OF ACH BY THE MOTOR
NEURON
Arrival of an AP at the axon terminal stimulates the opening
of voltage-gated Ca ion channels in the presynaptic plasma
membrane, causing the intracellular concentration of free Ca
ions to increase 10-100 times
The increase in Ca ion concentration triggers the binding of
synaptic vesicles (each containing 5000 molecules of Ach =
quantum or minimum packet) to the presynaptic membrane
137. SIGNAL FOR RELEASE OF ACH BY THE MOTOR
NEURON
Ach is rapidly removed from the synaptic cleft after its
release
In order to control the transmission of information between
the presynaptic & postsynaptic membranes
There is rapid diffusion of Ach in the synaptic cleft
Ach is hydrolysed to choline & acetic acid by
acetylcholinesterase
Acetylcholinesterase is produced by the muscle cell & is
anchored to its basal lamina by a protein
138. CLINICAL CONDITIONS WITH NEUROMUSCULAR JUNCTION
DYSFUNCTION
Alpha-Bungarotoxin (found in the venom of the
Formosan snake) & curare (from a plant-derived
American Indian arrow poison) can bind to this Ach
receptor preventing the opening of the ion channels thus
blocking postsynaptic AP → skeletal muscle paralysis
The autoimmune disease myasthenia gravis is a
neuromuscular disorder in which antibodies that bind to
Ach receptor are produced leading to destruction of
these receptors & loss of muscular function
139. CLINICAL CONDITIONS WITH
NEUROMUSCULAR JUNCTION DYSFUNCTION
The anaerobic bacterium Clostridium botulinum produces
botulinum type B toxin that also causes skeletal muscle
paralysis.
The botulinum toxin cleaves synaptobrevin, which is found
on the surface of synaptic vesicles & is required for their
fusion with the presynaptic plasma membrane, thus blocking
the delivery of Ach into the synaptic cleft
Organophosphate insecticides, the alkaloid eserine,
physostigmine all inhibit the action of acetylcholinesterase &
thus cause muscular paralysis (in a state of contraction)
140. MUSCLE MECHANICS
• A muscle twitch is a brief muscular contraction which is
immediately followed by relaxation in response to a single
stimulus
• Latent period – contractile mechanism has not yet been
activated, so no tension is produced, but an AP moves over the
sarcolemma & Ca ions are released from the SR
• The contraction phase – the tension in the whole muscle
gradually rises to a peak over 10-100 msec. Due to the
development of actin-myosin cross-bridges
• The relaxation phase – tension returns to resting levels
(50msec). Due to detachment of myosin-actin cross-bridges
141. MUSCLE MECHANICS
Isometric contraction – tension is developed with
no measurable external shortening of muscle
Isotonic contraction – occurs when one point of
attachment is not held fixed & muscle contraction
exhibits a simultaneous change in length
(shortening). These are the muscle contractions that
produce locomotion in animals
142.
143.
144.
145. MUSCLE MECHANICS
• Treppe – is observed when a rested muscle is
repeatedly stimulated with stimuli of equal intensity;
the first several twitches produce progressively
stronger contractile forces. This is due to increased
release of Ca ions from the SR → greater
availability of Ca ions to bind troponin C. If these
repetitive stimuli & contractions continue,
contractile tension will eventually decrease as
fatigue occurs
146.
147. TETANY
When a muscle receives repeated stimuli at such a rapid rate
that it cannot relax completely between contractions, a
summation of twitches occurs .
During this summation, if incomplete relaxations are evident
between contractions, the muscle is in incomplete tetany
When there is no relaxation at all between stimuli, the muscle
twitches fuse into one prolonged contraction (complete
tetany)
148. TETANY
In tetany Ca ions are released from the SR faster
than they can be pumped back in, owing to the rapid
train of AP’s.
Consequently, the cytoplasmic levels of Ca ions are
kept at a level above the threshold required for
muscle contraction