Neuromuscular Junction and Motor End Plate

• Skeletal muscle fibers are innervated by large α-myelinated nerve fibres

α-motor neuron branches

• As the α-motor neuron branches, it approaches the muscle
• The motor neuron ends in expanded endings called axon terminals, otherwise known as end feet or terminal buttons
• The tips of each branch (sole feet) are covered by the neurolemma

Neuromuscular Junction

• Neuromuscular junction is the area of contact between the nerve fiber and the muscle fiber
• There is no cytoplasmic continuity between the nerve and the muscle
• The axon loses its myelin sheath
• Each skeletal muscle fiber receives only one axon terminal
• Each nerve ending makes a junction, called neuromuscular junction

Motor End Plate

• At the neuromuscular junction, the neurilemma becomes continuous with the sarcolemma
• The muscle membrane is thickened and is called motor end plate
• The muscle membrane under the sole feet is invaginated to enclose them, called the synaptic gutter

Synaptic Cleft

• The space between the sole feet and the muscle fiber membrane is called the synaptic cleft, otherwise known as synaptic space, and is 25 nM wide.
• At the bottom of the gutter are numerous smaller folds of the muscle membrane called subneural clefts, increasing surface area where the synaptic transmitter can act.

Acetylcholine

• The sole foot contains many vesicles filled with acetylcholine (Ach); the chemical transmitter and many mitochondria which is necessary for its synthesis.
• Proteins called synapsin anchor the Ach vesicles to the cytoskeleton of the presynaptic terminal

Dense Bars

• On the inside surface of the neural membrane are linear dense bars
• Voltage-gated calcium channels are to each side of each dense bar

Cholinesterase

• At the border of the gutter, there is a large quantities of the enzyme cholinesterase, which hydrolyzes Ach
• It destroys Ach a few msec after it has been released from the synaptic vesicles
• The short time that the Ach remains in the synaptic space is sufficient to excite the muscle fiber
• About 60% of the released Ach is hydrolyzed before reaching the Ach receptors
• The remaining 40% is hydrolyzed after activating the channels
• Choline is taken up again by the nerve ending to form new Ach, and acetate escapes to the blood stream
• Rapid removal of Ach prevents continued muscle re-excitation

Miniature End Plate Potential (M.E.P.P.)

• M.E.P.P. is a state of persistent localized subthreshold DP (0.5 mV in amplitude) of the muscle fibres at the M.E.P. during rest
• It does not reach the firing level, so it does not lead to an AP
• The cause of this is due to the continuous release of small amounts of Ach (due to continuous rupture of a few vesicles that contain this chemical transmitter at the nerve terminals).

Mechanism of Neuromuscular Transmission

• Action potential propagates down a motor neuron
• Voltage-gated Ca++ channels open in terminal buttons
• Subsequently causing a Ca++ influx
• Synapsin proteins are phosphorylated, which anchor the Ach vesicles to the cytoskeleton of the presynaptic terminal
• Ach vesicles are freed from the cytoskeleton and are allowed to move to the active zone of the presynaptic neural membrane adjacent to the dense bars.
• The vesicles dock at the release sites, fuse with the neural membrane, and empty their Ach into synaptic space via exocytosis.
• About 125 vesicles of Ach are released from the terminals into the synaptic space.
• Acetylcholine diffuses across the cleft
• Binds to specific nicotinic Ach receptors in the muscle membrane
• Na+ and K+ channels open, these are ligand-gated
• More Na+ than K+ diffuses (more Na+ ions flow than K+ ions)
• Development of end plate potential and the formation of end plate potential result.
• When EPP reaches the firing level, an AP is generated
• Ach then detaches from receptors
• Ach then diffuses into the folds of MEP
• Ach is then rapidly hydrolyzed by cholinesterase, which prevents re-excitation of the muscle
• This process is the termination of Ach action

End Plate Potential (E.P.P.)

• A state of nonpropagated transient DP of the postjunctional membrane of the motor end plate
• Follows the arrival of an impulse to the motor nerve ending
• It is a state of partial DP
• When EPP reaches the firing level, an AP is generated

Properties of Neuromuscular Transmission

• Transmission of impulse is Unidirectional; they are allowed to pass from the nerve to the muscle.
• Transmission of impulses at the MEP is delayed by 0.5 mS
• This time is needed for:
  • Release of the Ach.
  • Its diffusion through the synaptic cleft and combination with the its receptors. -Na + influx till the firing level is reached
• It is easily fatigued by repeated stimulation mostly due to exhaustion of Ach.
• There is also an effect by ions:
  • Excess Ca++ causes increased release of Ach and increase transmission due to rupture of Ach vesicles.
  • Excess Mg++ causes decreased release of Ach and decreased transmission due to block rupture of vesicles.

Drugs That Stimulate Neuromuscular Transmission

• Act by Acetylcholine-Like Action: these are not rapidly hydrolyzed by cholinesterase enzyme, for e.g. methacholine and carbachol.
• Inactivating Acetylcholinesterase: these drugs preserve the liberated Ach at the MEP, for e.g. neostigmine, physostigmine (eserine).

Drugs That Block Neuromuscular Transmission

• Curare (tubocurarine) and some other related drugs (e.g. Flaxedil) block the action of Ach by occupying its receptors at MEP (competitive inhibition).
• These drugs are used as muscle relaxants during surgical operations
• Botulinum toxin inhibits the release of Ach
• Clostridium botulinum is specific bacteria that cause potent botulinum toxins
  • These act by preventing the release of neurotransmitters in the CNS and at the neuromuscular junction which causes flaccid paralysis.
  • Botulism can result from ingestion of contaminated food or wound infection.
• Hemicholinium blocks the reuptake of choline into nerve terminals, thereby depleting stores of Ach.

Conditions and Drugs that Affect Neuromuscular Transmission

• Acetylcholine-Like Action: methacholine and carbachol stimulate Neuromuscular Transmission
• Curare blocks nicotinic receptors at MEΡ, hindering the binding of acetylcholine to receptors
• Myasthenia gravis destroys Ach receptors
• Affect Acetylcholinesterase: Eserine and prostagmine (a drug) inhibit acetylcholinesterase

Myasthenia Gravis

• Hereditary disease that affects females more than males
• Characterized by marked progressive weakness and easy fatigability of muscles

Myasthenia Gravis Cause

• Due to the formation of autoantibodies (autoimmune) that cause the destruction of Ach receptors at the MEP, the response to Ach is reduced
• treated by drugs which inhibit cholinestrase e.g. prostagmine thereby preserving Ach which leads to better neuromuscular transmission and prolongs the action of ACh at the ΜΕΡ
  • Eserine is NOT used in the treatment because, besides muscle contraction, it produces dangerous parasympathetic effects like hypotension due to V.D. and bradycardia.
• excessive salivation, defecation and micturition

Drug interactions

• The antagonist of eserine is atropine
• The antagonist of atropine is either Ach or eserine

Lambert-Eaton syndrome

• Neuromuscular disease that has symptoms of progressive muscle weakness and fatigue
• Caused by circulating antibodies to presynaptic Ca2+ channels, prevents nerve terminals preventing DP and release of Ach.