Chapter 11: Neuromuscular Physiology
The Neuromuscular Physiology
The Neuromuscular Junction (NMJ)
• A synapse that develops between a motor
neuron and a muscle fiber
• Made up of several components:
- The presynaptic nerve terminal,
- The postsynaptic muscle membrane on the
muscle membrane
- The intervening cleft (or gap)
Muscles
Muscle composes 45% to 50% of total body mass,
with skeletal muscles accounting for
approximately 40% of body mass.
Muscle cells are highly specialized cells for the
conversion of chemical energy into mechanical
energy.
Muscle types
• Muscles are generally classified as skeletal,
smooth, or cardiac.
• Skeletal and cardiac muscles are striated
muscles and they share a common basic
organization of the contractile filaments but
they have different histologic and functions.
Skeletal Muscle
- Shape: multinucleated and tubular
- Responsible for voluntary actions
Cardiac Muscle
- Shape: May be mono- or binucleated. Branched,
and contain intercalated discs.
- Subserve functions related to the
cardiovascular, respiratory,
gastrointestinal,
and genitourinary systems
• Inappropriate activity of smooth muscle is
involved in hypertension, atherosclerosis,
asthma, and disorders of the gastrointestinal
tract.
Motor Units
The Neuromuscular Junction (NMJ)

• Vertebrate skeletal muscles are

• Comprises of three structures:
innervated by large myelinated α motor
- Motor neuron
neurons that originate from cell bodies
- Muscle fiber
located in the brainstem or ventral
- Glial cells Schwann cells
(anterior) horns of the spinal cord

*The formation, differentiation, and

• The motor unit is the functional
function of the NMJ require a proper
contractile unit
interaction (cross talk) between the nerve
terminal and muscle cell. Failure of this
• The motor unit is composed of a single
cross talk will result in a wide spectrum
myelinated α motor neuron and all
of neuromuscular disorders.
muscle fibers that receive innervation
from this single neuron.
• The NMJ is designed to transmit
electrical impulses from the nerve
• A large motor nerve innervates more
terminal to the skeletal muscle via the
muscle fibers than a smaller motor nerve
chemical transmitter, acetylcholine
does.

• A small motor unit innervate the “red

slow” muscle fibers, whereas large motor
units innervate the “white or pale
fast” muscle fibers.

• The slow muscle fibers appear red (eg,

masseters) as a result of high contents
of myoglobin, mitochondria, and
capillaries. the red fibers are
resistant to fatigue

• White muscle fibers (eg, psoas muscle)

• The NMJ structure consist of:

- The presynaptic (or prejunctional)

nerve terminal containing synaptic vesicles
(SVs) (filled with acetylcholine) and
mitochondria.

- The synaptic cleft that contains basal

lamina to which acetylcholinesterase enzyme
responsible for hydrolysis of free
acetylcholine is attached.

- The postsynaptic (or postjunctional)

muscle membrane that opposes the nerve
terminal is highly infolded and these folds
are called secondary folds (or secondary
postsynaptic cleft)
 Presynaptic Region
Synaptic Vesicles (VS)

• The SVs are specialized secretory

organelles.

• The SVs are synthesized in the neuronal

cell body in the endoplasmic reticulum.

• The SVs are then loaded with

acetylcholine in the motor nerve endings.

• The nAChRs are concentrated at the

crests of these folds (directly
opposing the active zones of the
presynaptic membrane in which SVs are
clustered), and voltage-gated sodium
The SVs possess a diverse set of specialized
channels are present in the troughs of
proteins divided into two functional classes:
the folds.

1. Proteins involved in the uptake of

neurotransmitters (transport proteins)
• Synaptic plasticity is the “ability of
individual synaptic junctions to
2. Proteins that mediate SV membrane
respond [ie, to change in strength in
traffic such as docking, fusion, and
response] to either use or disuse.
budding
The plasticity of neuromuscular
• Calcium ion signaling plays a pivotal
transmission is dependent on a mechanism
role in the process of acetylcholine
involving:
vesicles exocytosis
(1) Synthesis, storage, and release of
acetylcholine from the presynaptic region
at the NMJ.

(2) Binding of acetylcholine to nicotinic

receptors on the muscle membrane
(postsynaptic region) and generation of
action potentials.

(3) Rapid hydrolysis of acetylcholine by

the enzyme acetylcholinesterase, which is
present in the synaptic cleft.

(4) Adaptation of the muscle contractile

proteins to functional demands.

Acetylcholine (ACh)
• An important neurotransmitter that
plays a role in brain functions,
such as memory, and body functions,
such as muscle contractions to move
the muscles.
• ACh first synthesized in the cytoplasm
of the nerve terminal from acetyl
coenzyme A and choline in a reaction
catalyzed by the soluble enzyme choline
acetyltransferase.
• An energy-dependent “transporter”
then accumulates acetylcholine
within vesicles.
• Each vesicle contains 5,000 to
10,000 molecules of acetylcholine.
• The acetylcholine contained in a
single vesicle is often referred to
as a “quantum” of transmitter
• Nearly 50% of the released
acetylcholine is rapidly hydrolyzed
by the acetylcholinesterase during
diffusion across the synaptic cleft
before reaching the postsynaptic
receptors.
• The products of this hydrolysis are
choline and acetate.
• Choline is recycled into the
terminal by a high-affinity uptake
system, making it available for the
re-synthesis of acetylcholine.
• After exocytosis, the membrane
components of the SVs are recovered
by endocytosis and recycled for
future use.
Synaptic cleft.
• It separates nerve and muscle fiber
plasma membranes and is encompasses the
synaptic basal lamina and is filled with
extracellular fluid.
• The synaptic cleft is <20 to 50 nm wide.
• Acetylcholinesterase enzyme is bound to
the basal lamina at the cleft.
• Acetylcholinesterase is highly
concentrated at the NMJ but present in a
lower concentration throughout the length
of muscle fibers
• Acetylcholinesterase is regulated, in
part, by muscle activity and by the
spontaneous or nerve-evoked
depolarization of the plasma membrane
• After denervation, there is a large
decrease in the density of
acetylcholinesterase molecules. In
addition to hydrolysis of acetylcholine,
acetylcholinesterase has other functions
such as nerve growth–promoting
activities13 and modulation of nAChRs.
• Acetylcholinesterase ranks as one of the
most efficient catalytic processes known.
• The efficiency of acetylcholinesterase
depends on its fast activity.
• It can catalyze acetylcholine hydrolysis
(4,000 molecules of acetylcholine
hydrolyzed per active site per second) at
near diffusion-limited rates.
 The Nicotinic Acetylcholine Receptor
(nAChR) at the Neuromuscular Junction
• nAChRs are highly concentrated
(<10,000/μm2) at the crests of
junctional folds and in close proximity
to acetylcholine-releasing sites.
• The AChR expression and clusters are
both regulated by positive and negative
signals from the nerve and muscle.
• The nAChR is a pentameric complex of
two α subunits in association with a
single β, δ, and ε subunit
• These subunits are organized to form a
transmembrane pore (a channel) as well
as the extracellular binding pockets for
acetylcholine and other agonists or
antagonists.
• Each of the two α subunits has an
acetylcholine-binding site.
• The fetal nAChRs are different from
postnatal ones in composition and electric
properties.
- It contains a γ subunit instead of an ε
adult subunit.
- The mature nAChR has shorter burst
duration and a higher conductance to
sodium ion, potassium ion (K+), and
calcium ion than the fetal nAChR
• The fetal nAChR is a low-conductance
channel in contrast to the high-conductance
channel of the adult nAChR. Thus,
acetylcholine release causes brief
activation and reduced probability of
channel opening.
• Upregulation of nAChRs, found in states of
functional or surgical denervation, is
characterized by the spreading of
predominantly fetal type nAChRs. These
receptors are resistant to nondepolarizing
neuromuscular blockers and more sensitive
to succinylcholine (SCh). When depolarized,
the immature isoform has a prolonged open
channel time that exaggerates the K+ efflux
• Simultaneous binding of two acetylcholine
molecules to the extracellular N-terminal
domain of the two α subunits of nAChRs
initiates conformational changes that open
a channel through the center of the
receptor, allowing sodium and calcium ions
to move into the skeletal muscle and K+ to
leave
• Each NMJ contains several million
postjunctional receptors, and a burst of
acetylcholine from the nerve ending opens
at least 400,000 receptors. As a result,
sufficient current flows through these open
receptors to depolarize the endplate and
create the action potential that triggers
contraction of the skeletal muscle.
• The two α subunits, in addition to being
the binding sites for acetylcholine, are
occupied by neuromuscular-blocking drugs.
• Nondepolarizing neuromuscular-blocking
drugs bind to one or both α subunits but,
unlike acetylcholine, lack agonist
activity (competitive blockade).
- As a result, conformational changes do
not occur, and the receptor channel
remains closed. Therefore, ions do not
flow through these channels, and
depolarization cannot occur at these
sites.
***If enough channels remain closed, there is
blockade of neuromuscular transmission.
• A non-depolarizing neuromuscular-blocking
drug may show preference for one of the
two α subunits.
- This may result in synergism if two
non-depolarizing neuromuscular-blocking
drugs with different selective
preferences for each α subunit are
administered simultaneously
• The other α subunit can be occupied by
either acetylcholine or SCh.
• Because SCh is not hydrolyzed by
acetylcholinesterase, the channel
remains open for a longer period of time
than would be produced by acetylcholine,
resulting in a depolarizing block
(sustained depolarization prevents
propagation of an action potential)
• Furthermore, SCh can diffuse from nAChRs
and repeatedly bind to other nAChRs
until it is cleared from the area of the
NMJ and is exposed to hydrolysis by
plasma cholinesterase.
• Large doses of non-depolarizing
neuromuscular-blocking drugs may also
prevent normal flow of ions by entering
the channels formed by nAChRs to produce
blockade within the channel. Similar
blockade of sodium ion channels is
produced by local anesthetics.

• The probability of binding is dependent

on the concentration of acetylcholine and
nondepolarizing neuromuscular-blocking
drug at the receptor and the affinity of
the receptor for the neurotransmitter or
drug.

• When the neuromuscular-blocking drug

diffuses from the nAChRs, the probability
of receptor binding of acetylcholine
increases, and the effect of the
nondepolarizing neuromuscular-blocking
drug decreases.

• The SCh, which is structurally two

molecules of acetylcholine bound
together, is a partial agonist at nAChRs
and depolarizes (opens) the ion channels

- This opening requires the binding of

only one molecule of SCh to the α
subunit.
 Blood Flow
Skeletal muscle blood flow can increase more
than 20 times (a greater increase than in any
other tissue of the body) during strenuous
exercise.
• At rest, only 20% to 25% of the
capillaries are open, and skeletal muscle
blood flow is 3 to 4 mL/100 g/min.
• Opening of previously collapsed
capillaries diminishes the distance that
oxygen and other nutrients must diffuse
from capillaries to skeletal muscle fibers
and contributes an increased surface area
through which nutrients can diffuse from
blood.
- Exercise lowers the local concentration of
oxygen, which in turn causes vasodilation
because the vessel walls cannot maintain
contraction in the absence of adequate
amounts of oxygen.
- Alternatively, oxygen deficiency may
cause release of vasodilator substances
such as K+ and adenosine.
- The increase in cardiac output that
occurs during exercise results
principally from local vasodilation in
active skeletal muscles and subsequent
increased venous return to the heart.
• Exercise is associated with a centrally
mediated stimulation of the sympathetic
nervous system manifesting as
vasoconstriction in nonmuscular tissues
and increases in systemic blood pressure.
• Excessive increases in systemic blood
pressure, are prevented by vascular
vasodilation that occurs in the large
tissue mass represented by skeletal
muscles.
• Exceptions to non-muscular tissue
vasoconstriction induced by exercise are
the coronary and cerebral circulations.
This is teleologically understandable
because the heart and brain are essential
to the response to exercise, as are the
skeletal muscles.
Smooth Muscle
• Smooth muscle is distinguished
anatomically from skeletal and cardiac
muscle because it lacks visible cross-
striations (actin and myosin are not
arranged in regular arrays).
• Smooth muscle is categorized as
multiunit or visceral smooth muscle.
• Multiunit smooth muscle contraction is
controlled almost exclusively by nerve
signals, and spontaneous contractions
rarely occur.
- Examples of multiunit smooth muscles are
the ciliary muscles of the eye, iris of the
eye, and smooth muscles of many large blood
vessels.
• Smooth muscle must develop force or
shorten to provide motility or to alter
the dimensions of an organ.
• Smooth muscle cells lack T tubules that
provide electrical links to SR. However,
the sarcolemma of smooth muscle contains
saclike inpocketings (caveoli) that may
be sites where calcium ions enter the
cells through voltage-gated calcium ion
channels.
• Calcium ions are released from the SR
into the myoplasm when stimulatory
neurotransmitters, hormones, or drugs
bind to receptors on the sarcolemma.
• Calcium ion channels on the SR of smooth
muscles include RyR1 (similar to those
present in skeletal muscles) and
inositol 1,4,5-triphosphate (IP3)-gated
calcium ion channels.
• Neurotransmitters or hormones that act
via receptors in the sarcolemma can
activate phospholipase C followed by the
generation of the second messenger IP3.
• The IP3 channels are activated when
hormones bind to calcium-mobilizing
receptors in the SR in smooth muscle
cells.
 Mechanism of Contraction
• Smooth muscles contain both actin and
myosin.
• Smooth muscles are different from
skeletal muscles:
- They are innervated by autonomic
neurons
-They lack troponin.
• In contrast to skeletal muscles, in
which calcium binds to troponin to
initiate cross-bridging, in smooth
muscle, the calcium-calmodulin complex
activates the enzyme necessary for
phosphorylation of myosin.
- This myosin has ATPase activity,
and actin then slides on myosin to
produce contraction.
• The source of calcium in smooth muscle
differs from that in skeletal muscle
because the SR of smooth muscle is
poorly developed.
• Most of the calcium that causes
contraction of smooth muscles enters
from extracellular fluid at the time of
the action potential.
• The time required for this diffusion is
200 to 300 milliseconds, which is
approximately 50 times longer than for
skeletal muscles
• Subsequent relaxation of smooth muscles
is achieved by a calcium ion transport
system that pumps these ions back into
extracellular fluid or into the SR.
-This calcium ion pump is slow compared
with the SR pump in skeletal muscles. As
result, the duration of smooth muscle
contraction is often seconds rather than
milliseconds as is characteristic of
skeletal muscles
• Smooth muscles, unlike skeletal muscles,
do not atrophy when denervated, but they
do become hyper-responsive to the normal
neurotransmitter.
- This denervation hypersensitivity is a
general phenomenon that is largely due to
synthesis or activation of more
receptors.
• An NMJ that is similar to that present
on skeletal muscles does not occur in
smooth muscles. Instead, nerve fibers
branch diffusely on top of a sheet of
smooth muscle fibers without making
actual contact.
- These nerve fibers secrete their
neurotransmitter into an interstitial
fluid space a few microns from the
smooth
muscle cells.
• Two different neurotransmitters,
acetylcholine and norepinephrine, are
secreted by the autonomic nervous system
nerves that innervate smooth muscles.
• Acetylcholine is an excitatory
neurotransmitter for smooth muscles at
some sites and functions as an
inhibitory neurotransmitter at other
sites.
• Norepinephrine exerts the reverse effect
of acetylcholine.
 Uterine Smooth Muscle

• Uterine smooth muscle is characterized by a high degree of spontaneous electrical

and contractile activity.

• Unlike the heart, there is no pacemaker, and the contraction process spreads from
one cell to another at a rate of 1 to 3 cm/s.

• Contractions of labor result in peak intrauterine pressures of 60 to 80 mm Hg in

the second stage.

• Resting uterine pressure during labor is approximately 10 mm Hg.

• Movement of sodium ions appears to be the primary determinant in depolarization,

whereas calcium ions are necessary for excitation-contraction coupling.

• Availability of calcium ions greatly influences the response of uterine smooth

muscle to physiologic and pharmacologic stimulation or inhibition.

• α Excitatory and β inhibitory receptors are also present in the myometrium.