Sliding filament theory AF
Huxley and R Niedergerke,
1954
Tropomyosin and troponin regulate the
interaction between actin and myosin
proteins of thick and thin filaments
During contraction, cross-bridges attach
between actin and myosin
Two filaments slide over each other when
energy is provided by the hydrolysis of
ATP
Neuromuscular Bases of
Contraction
Skeletal muscle contracts only after
stimulation from a motor neuron
Normally, each motor neuron branches
several times and stimulates a few to
several hundred muscle fibers
Motor Unit
Motor neuron, (cell, etc.)
Muscle fibers it innervates
Site: neuromuscular junction,
motor end plate, myoneural
junction
Contraction begins
Initiation of the action potential by the
motor neuron
Transmission of the AP across the motor
end plate to the muscle fiber
when AP reaches
neuromuscular junction
~ 200-300 vesicles of acetycholine (ACH,
neurotransmitter) are released into the gap
between the motor neuron and the motor
end plate (cleft)
and reacts with receptor
molecules in the sarcolemma
Reaction causes an increase in
permeability to sodium ions, resulting in
depolarization of the sarcolemma or endplate potential
If end-plate potential is large enough to
exceed a threshold (depending on skeletal
muscle type), the nerve impulse will be
successfully transformed into a muscle
impulse
The impulse travels in all directions over
the muscle membrane when being
transmitted
Deep into the fiber through the transverse
tubules (t-tubules)
ACH is released from the vesicles
and diffuses across the cleft
binds with receptor, increasing the
permeability of the sarcolemma to sodium
ions
depolarizing the sarcolemma (end-plate
potential)
Impulse travels down t-tubules, all over
membrane to transverse tubules
As the AP is transmitted throughout the
fiber, the membranes of the cisterane in
the SR become more permeable to Ca++
and the stored ions diffuse into the
sarcoplasm of the fiber
Once the Ca++ concentration is high
enough, (100X increase, 10-5 M), the Ca++
binds with the TnC molecule
Binding of Ca++ to the TnC causes a
positional change of the Tn, which also
effects the positioning of the tropomyosin,
moving it deeper into the groove between
the two actin strands
TnC
Two different isoforms
One specific to fast muscle
One specific to slow muscle
Fast contain two binding sites for Ca++
Site I and site II
Slow have only one binding site
both sites must be filled to trigger
contraction
Conformational Change
there is a conformational change with binding
that exposes a hydrophobic cavity (the TnI
binding site).
Alters the interaction between TnI and TnC
Instead of TnI binding to actin, it preferentially
switches to binding domain on TnC, allowing
actin and myosin to interact.
Slow and Cardiac Muscle
Slow skeletal muscle has no site I
Slow and cardiac muscle are activated by
one, not two calcium ions by the TnC
isoforms subunit.
Therefore, contraction frequency, power
output, and strength are typically down
regulated
all of the characteristics of these subunits and
their role in contraction are not yet clear
(e.g., Tn complex may attach the tropomyosin
to the actin) do know that each subunit plays
a role in the contractile process
Actin binding sites
Uncovered, actin and myosin can interact
ATPase activity of myosin head
immediately hydrolyzes ATP
Conformation of the head is that it extends
perpendicularly towards the actin filament
at this time
The products of the hydrolysis (ADP and Pi)
remain bound to the head, which is now
“energized” with the energy released from the
reaction
Myosin head now interacts with the binding sites
on the actin filament
When actin and myosin bind, forming an
actomyosin complex, the stored energy is
released
This release of energy alters the
position of the myosin head and
produces force through the cross-bridge
movement
the head tilts toward the arm of the
cross bridge, providing the power stroke
for pulling the actin
the energy activating the power stroke
is the energy already stored, like a
cocked spring, by the conformational
change in the head when the ATP
molecule cleaved
when the head attaches to the active
site, there are changes in the
intramolecular forces between the head
and the arm of the cross-bridge
this alignment of forces causes the
head to tilt toward the arm and to drag
the actin filament along with it
this tilt of the head is called the power
stroke, and causes the release of ADP
and Pi
immediately after tilting, the head
automatically breaks away from the
active site, binding an ATP
the head returns to the perpendicular
position
once head is detached, a new molecule of
ATP is hydrolyzed by the myosin ATPase,
energizing the head again so cycle can
repeat
In this new position, it binds with a new
actin binding site
heads of cross-bridges bend back and
forth, step by step, walking along the
actin filaments toward the center of the
myosin
each myosin acts independent of each
other, each attaching and pulling in a
continuous but random cycle
the greater the number of cross-bridges
in contact with actin at any given time,
the greater the theoretical force of
contraction
because of the orientation of the actin and
myosin, the actin filaments move towards each
other, the Z lines move closer together and the H
zone disappears
this process will continue until the Z membrane
is pulled against the myosin filament or until the
load on the muscle becomes too great for further
pulling to occur (assuming muscle stimulation is
still occurring)
Single Contraction Cycle
Contraction cycle of myosin cross-bridges
of a muscle shortens a muscle by 1% of its
resting length
consequently, the contraction cycle must
be repeated over and over to significantly
shorten the whole muscle
Fenn Effect
When a new ATP attaches to a myosin
head, the cross-bridge can detach from
the actin and the greater amount of work
performed by the muscle, the greater
amount of ATP which is cleaved
ACH
at same time contraction is occurring, ACH that
stimulated the contraction is being rapidly
decomposed by the action of cholinesterase
(enzyme present at the myoneural junction
within the membranes of the motor end plate)
rapid removal of ACH insures that a single nerve
impulse will not cause a continued stimulation of
the muslce
Impulse Duration
Usual duration of an impulse to skeletal
muscle is about 20 milliseconds
in order for contraction to continue, there
must be continual stimulation of the
muscle fiber
the signal to stop contraction is the
absence of a nerve impulse at the junction
AP stops
continually active calcium pump located
in the walls of the SR pumps the
calcium ions out of the sarcoplasm and
back into the SR via the fenestrated
collar, and then the calcium diffuses
back into the cisternae
this lowers the concentration of calcium,
removing it from the TnC, the
Tn/tropomyosin complex returns to its
original conformation and the active
sites are covered
fiber returns to its relaxed position