NERVE AND MUSCLE VETERINARY PHYSIOLOGY .pdf

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)

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.

 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

 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

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

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

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

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

 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

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.

 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.

 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 (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.

• 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.

• 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

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 & 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

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 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 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.

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 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 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

 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

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

• 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 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

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

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)

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

 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

• 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)

 Clostridial neurotoxins are proteases that prevent
neurotransmitter release through cleavage of
synaptobrevin (botulinum toxin), SNAP-25 or
syntaxin

 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

• 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.

 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)

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

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

 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

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

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)

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

 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)
MUSCLE

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

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

 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

 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)

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

 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.

 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.

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

 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)

 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

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

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.

SMOOTH MUSCLE
 Smooth muscle lacks neuromuscular junctions,
but have varicosities
 Varicosities- numerous bulbous swellings that
release neurotransmitters to a wide synaptic cleft.

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

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

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.

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

SMOOTH MUSCLE CONTRACTION
• Source of Calcium
i. ECF Ca2+ entering
through Ca2+ channels
ii. Ca2+ from SR

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

COMPARISON: SMOOTH & SKELETAL MUSCLE CONTRACTION

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

 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)

• 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

 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

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

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

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

 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

 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

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

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

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

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)

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

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

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

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)

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

NERVE AND MUSCLE VETERINARY PHYSIOLOGY .pdf

NERVE AND MUSCLE VETERINARY PHYSIOLOGY .pdf

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NERVE AND MUSCLE VETERINARY PHYSIOLOGY .pdf