NEURO-MUSCULAR Junction and SKELETAL muscular contraction DR.RAHUL
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Transcript of NEURO-MUSCULAR Junction and SKELETAL muscular contraction DR.RAHUL
NEURO-MUSCULAR JUNCTION & MECHANISM OF SKELETAL
MUSCLE CONTRACTION
by Dr. Rahul M.D.Final year (Physiology) ,SMS Medical
College Jaipur
FIGURE 6–13 The neuromuscular junction. (a) Scanning electronmicrograph showing branching of motor axons with terminals embedded in grooves in the muscle fiber’s surface. (b) Structure of a neuromuscular junction. (From Widmaier EP, Raff H, Strang KT: Vanders Human Physiology.McGraw-Hill, 2008.)
We begin with Neuromuscular Junction
The neuromuscular junction is the synapse
between a motor neuron and a skeletal muscle cell.
At the endplate, the motor neuron axon
arborizes into numerous terminal boutons that
contain large numbers of ACh-filled vesicles.
ACh is synthesized in the boutons from choline
and acetyl coenzyme A by choline
acetyltransferase.
ACh then is pumped into the vesicles by a
specific ACh-H+ exchanger.
The basal lamina between the presynaptic and
postsynaptic membranes contains a high
concentration of the degradative enzyme AChE.
Case files Physiology: EUGENE C.TOY :LangeMc Graw Hills:2nded: 42-44
SYNTHESIS OF Acetyl choline
Ach H+ exchanger
Acetyl choline is synthesized within the mitochondria
from Choline in presence of choline acetyltransferase.
The storage vesicles and choline acetyltransferase are
produced in the soma and are transported to the axon
terminals.
The rate-limiting step in ACh synthesis in the nerve
terminals is the availability of choline, of which specialized
mechanisms ensure a continuous supply
(Medical physiology principles of clinical medicine :Rhodney A Rhoades : Lippincott : 4rth ed : chap3: pg 55)
(Source:Ganong’s Medical Physiolog /TMH /24thed/Fig 5-7pg 104)
(Source: Ganong’s Medical Physiolog /TMH /24thed/chap 6 /122)
They involve the v-snare protein synaptobrevin in the
vesicle membrane locking with the t-snare protein
syntaxin in the cell membrane; a multiprotein complex
regulated by small GTPases such as rab3 is also
involved in the process.
Source:Ganong’s Medical Physiology /TMH /24thed/chap6/pg 121
Several toxins which block neurotransmitter release
are zinc endopeptidases that cleave and hence
inactivate proteins in the fusion–exocytosis complex.
Tetanus toxin and botulinum toxins B, D, F, and G
act on synaptobrevin
Botulinum toxin C acts on syntaxin
Botulinum toxins A and B act on SNAP-25.
Clinical implications :
Clinically, tetanus toxin causes spastic paralysis by
blocking presynaptic transmitter release in the CNS.
Botulism causes flaccid paralysis by blocking the
release of acetylcholine at the neuromuscular junction.
Source: Ganong’s Medical Physiology /TMH /24thed/chap6/pg 123
local injection of small doses of botulinum toxin
(botox) is efficacious in the treatment of various
conditions like Lower esophageal sphincter to relieve
achalasia and injection into facial muscles to remove
wrinkles
?A 18-year-old college woman comes to the student
health service complaining of progressive
weakness.
She reports that occasionally her eyelids “droop”
she tires easily, even when completing ordinary
daily tasks such as brushing her hair.
She has fallen several times while climbing a flight
of stairs.
These symptoms improve with rest.
Treated with the drug pyridostigmine.
After treatment, she reports a return of muscle
strength
The physician orders blood studies, which reveal
elevated levels of antibodies to ACh receptors.
Nerve stimulation studies show decreased
responsiveness of skeletal muscle on repeated
stimulation of motor neurons. The woman is diagnosed with Myasthenia Gravis
(Source: Physiology : Linda Costanzo/Elsevier/ 5th ed/pg.28)
Myasthenia Gravis
Though ,release of Ach remains normal, but
reduction in the number of receptors, the EPP is
reduced and may fail to reach threshold for muscle
action
Antibodies are produced to ACh receptors on the
motor end plates of skeletal muscle that block ACh
receptors.
Autoimmune form of the neuromuscular disease.
Common in females, with peak incidence at 20 to 30
years of age.
Thus , more normal EPP in the muscle fiber can be
produced even though many of the ACh receptors
are blocked by antibodies.
Muscle weakness and fatigability ensue.
AChE on the motor end plate normally degrades ACh
By inhibiting the AChE with pyridostigmine, ACh
levels in the neuromuscular junction are
maintained at a high level prolonging the time
available for ACh to activate its receptors on the
motor end plate.
Lambert–Eaton Syndrome
Muscle weakness is caused by an autoimmune attack
against one of the Ca2+ channels in the nerve endings at
the neuromuscular junction.
This decreases the normal Ca2+ influx that causes
acetylcholine release.
Proximal muscles of the lower extremities are
primarily affected, producing a waddling gait and
difficulty raising the arms.(Source:Ganong’s Medical Physiolog /TMH /24thed/Fig 5-7pg 104)
venom of black widow spider exerts its effect by
triggering explosive release of Ach from the storage
vesicles, not only at N.M junction but all cholinergic
sites. All cholinergic sites undergoes prolong
depolarization.
Agents that alters the function of N.M junction
Black widow spider venom :
Source: Human Physiology: Vander et al: The Mechanism of Body Function McGraw−Hill Companies 2001/8th Ed : Chap:11: Pg 307
Curare
competitively binds to ACh receptors not allowing
Ach to bind so no opening of ion channels
curare not destroyed by acetylcholinesterase.
Though motor nerves conducting normal action
potentials and release ACh, there is no EPP in the
motor end plate and hence muscles paralysis.
curare poisoning leads to death by asphyxiation
Used as arrowhead poison
(Source: Physiology : Linda Costanzo/Elsevier/ 5th ed/pg.34 )
Source: Human Physiology: Vander et al: The Mechanism of Body Function McGraw−Hill Companies 2001/8th Ed Chap:11 : Pg :297
Titin is a prominent target for mutations that give
rise to muscle disease .
Mutations that encodes for shorter titin stucture
have been associated with Dilated Cardiomyopathy.
Skeletal muscle associated Tibialis muscular
dystrophy is a genetic muscle disease of titin .
Source: Ganong’s Medical Physiology /TMH /24thed/chap5/pg 100
Clinical Pearls
The process by which depolarization of the
muscle fiber initiates contraction is called
excitation–contraction coupling.
The action potential is transmitted to all the fibrils
in the fiber via the T system.
It triggers the release of Ca 2+ from the terminal
cisterns, the lateral sacs of the sarcoplasmic
reticulum next to the T system.
Depolarization of the T tubule membrane activates the
sarcoplasmic reticulum via dihydropyridine receptors
(DHPR), named for the drug dihydropyridine, which blocks
them .
DHPR are voltage-gated Ca2+channels in the T tubule
membrane.
In cardiac muscle, influx of Ca2+via these channels
triggers the release of Ca2+stored in the sarcoplasmic
reticulum (calcium induced calcium release) by activating the
ryanodine receptor (RyR).
RyR is named after plant alkaloid ryanodine . It is a
ligand-gated Ca2+channel with Ca 2+as its natural
ligand.
In skeletal muscle, Ca 2+entry from ECF by this
route is not required for Ca 2+release.
DHPR serves as voltage sensor ,unlocks release
of Ca 2+ from the nearby sarcoplasmic reticulum via
physical interaction with the RyR.
Terminal cisternae (Lateral sacs)contains a protein,
calsequestrin, that weakly binds calcium, storing
calcium in bound form maintaining a low free calcium
concentration in the sarcoplasmic reticulum.thereby
reducing the work of Ca ATPase pump.
Ca 2+is reduced in the muscle cell by the
sarcoplasmic or endoplasmic reticulum Ca2+
ATPase (SERCA) pump.
SERCA pump uses energy from ATP hydrolysis to remove
Ca2+ from the cytosol back into the terminal cisterns, where
it is stored until released by the next action potential.
Ca2+concentration outside the reticulum when lowered
sufficiently, chemical interaction between myosin and actin
ceases and the muscle relaxes.
ATP provides the energy for both contraction (at the
myosin head) and relaxation (via SERCA) .
Source:Ganong’s Medical Physiology /TMH /24thed/chap5/pg 103
Traced due to a mutation in RyR ( the Ca2+
release channel in the sarcoplasmic reticulum).
The mutation results in an inefficient feedback
mechanism to shut down Ca 2+ release after
stimulation of the RyR.
Malignant hyperthermia :
Anaesthetic agents like Halothane,exposure to
high enviornmental heat and strenous excercise
triggers abnormal release of ca2+ from
sarcoplasmic reticulum in muscle cell resulting in
sustained muscle contraction and heat generation
Source: Ganong’s Medical Physiology /TMH /24thed/chap5/pg 105
Interaction Between the “Activated” Actin Filament and the Myosin Cross-Bridges—The “Walk-Along” Theory(Ratchet Theory) OR Sliding Filament Theory of Contraction.
Discharge of motor neuron
Release of transmitter (Ach) at motor end-plate
Binding of Ach to nicotinic Ach receptors
Increased Na+ and K+ conductance in end-plate membrane
Generation of end- plate potential
Generation of action potential in muscle fibers
Inward spread of depolarization along T tubules
Release of Ca2+ from terminal cisterns of sarcoplasmic reticulum and diffusion to thick and thin filaments
Binding of Ca2+ to troponinC, uncovering myosin-binding sites on actin
Formation of cross-linkages between actin and myosin and sliding of thin on thick filaments, producing movement
Cessation of interaction between actin and myosin
Ca2+ pumped back into sarcoplasmic reticulum
Release of Ca2+ from troponin
steps of relaxation
(Source: Ganong’s Medical Physiolog /TMH /24thed/Fig 5-7pg 104)
A single action potential results in the release of a
fixed amount of Ca2+ from the sarcoplasmic reticulum,
which produces a single twitch.
The twitch is terminated (relaxation occurs) when
the sarcoplasmic reticulum reaccumulates this Ca2+.
However, if the muscle is stimulated repeatedly,
there is insufficient time for the sarcoplasmic
reticulum to reaccumulate Ca2+, and the intracellular
Ca2+concentration never returns to the low levels
that exist during relaxation.
MECHANISM OF TETANUS
(Source: Physiology : Linda Costanzo/Elsevier/ 5th ed/pg.38)
Source: HumanPhysiology: Vander et al: The Mechanism of Body Function McGraw−Hill Companies 2001/8th Ed : chap:11: Pg :313