NEUROMUSCULAR

PHYSIOLOGY
NEUROMUSCULAR
TRANSMISSION
 The nerve synthesizes acetylcholine and stores it
in small, uniformly sized packages called vesicles.

 Stimulation of the nerve causes these vesicles to

migrate to the surface of the nerve, rupture, and
discharge acetylcholine into the cleft separating
the nerve from muscle.

 AChRs in the end plate of the muscle respond by

opening their channels for influx of sodium ions
into the muscle to depolarize the muscle.
 The acetylcholine immediately detaches from the
receptor and is destroyed by the enzyme,
acetylcholinesterase, which is also present in the
cleft.

 NDMRs also act on the receptors, but they prevent

acetylcholine from binding to the receptor and thus
prevent depolarization by agonists.

 Because these NDMRs prevent the action of agonists

(e.g., acetylcholine, carbachol, succinylcholine), they
belong to the class of compounds known as
antagonists at the muscle AChRs.
 Other compounds, frequently called reversal
drugs or antagonists of neuromuscular paralysis
(e.g., neostigmine, prostigmine), inhibit
acetylcholinesterase and therefore impair the
hydrolysis of acetylcholine.

 The increased accumulation of undegraded

acetylcholine can effectively compete with
NDMRs and thereby displace the latter from the
receptor (i.e., law of mass action) and antagonize
the effects of NDMRs.
NEUROMUSCULAR JUNCTION
(NMJ)
 The neuromuscular junction (NMJ) or the
endplate is a highly specialized synapse at which
presynaptic motor nerve endings meet the
postsynaptic membranes of skeletal muscles
(motor endplates).

 The NMJ is designed to transmit electrical

impulses from the nerve terminal to the skeletal
muscle via the chemical transmitter,
acetylcholine (ACh).
 Each motor neuron runs without interruption
from the ventral horn of the spinal cord or
medulla to the neuromuscular junction as a
large, myelinated axon.

 As the motor neuron approaches the muscle, the

neuron repeatedly branches to contact many
muscle cells and gather them into a functional
group known as a motor unit.

 As the terminal reaches the muscle fiber, it loses

its myelin, forms a spray of terminal branches
against the muscle surface, and is covered by
Schwann cells.
 Structurally, the NMJ is consisted of a three
components:
(a) the presynaptic (or prejunctional) nerve
terminal containing synaptic vesicles (filled with
ACh) and mitochondria;

(b) the synaptic cleft: The nerve is separated from

the surface of the muscle by a gap of approximately
20 nm, called the junctional cleft or synaptic cleft.
 The nerve and muscle are held in tight alignment
by protein filaments called basal lamina that
span the cleft between the nerve and end plate.

 The muscle surface is heavily corrugated, with

deep invaginations of the junctional cleft—the
primary and secondary clefts—between the folds
in the muscle membrane; thus the end plate’s
total surface area is very large.

 The sodium channels, which propagate the wave

of depolarization, are located in the depths of the
folds
 and (c) the postsynaptic (or postjunctional)
muscle membrane that opposes the nerve
terminal.
A. Presynaptic Region
1. Synaptic vesicles are specialized secretory
organelles.
 Each vesicle appears to contain 5,000 to 10,000
molecules of acetylcholine.

 Nearly 50% of the released acetylcholine is

rapidly hydrolyzed by the acetylcholinesterase
during the time of diffusion across the synaptic
cleft .
The synaptic vesicle exocytosis–endocytosis
cycle.
The synaptic vesicle exocytosis–endocytosis
cycle.
B. Synaptic cleft separates nerve and muscle
fiber plasma membranes.
Acetylcholinesterase ranks as one of the highest
catalytic effi ciencies known (4,000 molecules of
acetylcholine hydrolyzed per active site per second)
at near diff usion-limited rates.
THE NICOTINIC ACETYLCHOLINE RECEPTOR
AT THE NEUROMUSCULAR JUNCTION

 In adult skeletal muscle the nicotinic

acetylchokine receptor (nAChR) is a pentameric
complex of two α subunits in association with a
single beta delta and e subunit.

 These subunits are organized to form a

transmenbrane pore as well as the extracellular
bining pockets for acetylcholine and othe
ragonists or antagonists.

 Each of the two alpha subunits has an

acetylchoine binding site.
 These sites are proteins located in pockets
approximately 3nm above the surface membrane
at the interfaces of the α-ε and α- δ subunits.

 The fetal nAChR contains a Ÿ subunit instead of

a ε adult subunit .

 The mature nAChR has shorter burst duration

and a higher conductance to Na+, K+, and Ca++
than the fetal nAChR.
 The fetal nAChR is a low conductance channell in
contrast to the high conductance channel of the
adult nAChR.

 Thus acetylchoine release causes brief activation

and reduced probability of channel opening.

 Upregulation of nicotinic acetylchoine receptors

found in states of functional or surgical
denervation is characterized by the spreading of
predominantly fetal type nAChR.

 These receptors are resistant to nondepolarizing

neuromuscular blocker and more sensitive to
succinylcholine.
 Simultaneous binding of two acetylcholine
molecules to the two alpha subunits of nAChR
initiates comformational chages that open a
channel through the center of the receptor alloing
sodium and clalcium ions to move into the
skeletal muscle and potassiumions to leave.

 Each NMJ contains several million

postjunctional receptors, and a burst of
acetylcholine from the nerve ending opens at
least 400000 receptors.
 As a result, sufficient current flows through these
open receptors to depolarize the endplate and
create the action potential that triggers
contraciton of the skeletal muscle.

 It is the flow of ions that is the basis of normal

neuromuscular transmission.

 The two alpha subunits, in addition to being the

binding sites for acetylcholine are the sites
occupied by neruomuscular blocking drugs.
1. Nondepolarizing neuromuscular blocking drugs
bind to one or both subunits, but unlike
acetylcholine, lack agonist activity (competitive
blockade).
a. As a result, conformational changes do not occur,
and the receptor channel remains closed.

b. 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.
2. SCh, which is structurally two molecules of
acetylcholine bound together, is a partial agonist at
nAChRs and depolarizes (opens) the ion channels.

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 form nAChR and
repeatedly bind to other nAChR until it is cleared
from the area of the NMJ and is exposed to
hydrolysis by plasma cholinesterase.
 Subunit composition of the nicotinic acetylcholine
receptor (nAChR) in the endplate surface of adult
mammalian muscle.
 The adult AChR is an intrinsic membrane
protein with five distinct subunits .
 Each subunit contains four helical domains
labeled M1 to M4. The M2 domain forms the
channel pore.
 The upper panel shows a single subunit with its
N and C termini on the extracellular surface of
the membrane lipid bilayer. Between the N and
C termini, the subunit forms four helices (M1,
M2, M3, and M4), which span the membrane
bilayer.
 The lower panel shows the pentameric structure
of the nAChR of adult mammalian muscle.
 The N termini of two subunits cooperate to form
two distinct binding pockets for acetylcholine.
 These pockets occur at the – and the – subunit
interface.
 The M2 membrane spanning domain of each
subunit lines the ion channel.
 The doubly liganded ion channel has equal
permeability to Na and K; Ca2 contributes
approximately 2.5% to the total permeability.
V. Neuromuscular Transmission and Excitation-
Contraction Coupling

A. Motor Nerve. Depolarization of the motor nerve will

open the voltage-gated Ca2 channels that trigger both
mobilization of synaptic vesicles and the fusion
machinery in the nerve terminal to release
acetylcholine.

B. Muscle
1. Th e released acetylcholine binds to subunits of the
nAChRs, causing a conformational shift in the subunits.
When the channel opens, sodium ions fl ow down their
electrochemical gradient and depolarize the muscle cell
membrane at the NMJ, whereas potassium
simultaneously exits.
 2. Th is depolarization activates voltage-gated sodium
 channels, which mediate the initiation and propagation
 of action potentials resulting in the upstroke of the
 action potential.
 C. Blood Flow. Skeletal muscle blood fl ow can increase more
 than 20 times (a greater increase than in any other tissue of
 the body) during strenuous exercise. Th e 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. Among inhaled
anesthetics,
 isofl urane is a potent vasodilator, producing marked
 increases in skeletal muscle blood fl ow.