Neuromuscular Transmission: LCS 105

• The academic year is 2024-2025, year 1, semester 2, and the module is locomotor system (LCS) 105
• Neuromuscular transmission involves Professor Dr. Mohamed Hassan Abdelsattar from the Faculty of Medicine at Al-Azhar University
• The department is medical physiology

Learning Objectives

• Explain the structure of a neuromuscular transmission
• Explain the end plate potential
• Explain the events that occur at the neuromuscular junction
• Summarize the properties of neuromuscular transmission
• Describe the ions and drugs that block neuromuscular transmission
• Describe the ions and drugs that stimulate neuromuscular transmission
• Define myasthenia gravis, explain its causes and treatment

Introduction

• Skeletal muscle fibres are innervated by large alpha-myelinated nerve fibres
• Alpha-motor neurons branch as they approach the muscle, ending in axon terminals (end feet or terminal buttons)
• The tips of each branch (sole feet) are covered by the neurolemma

Neuromuscular Junction (Motor End Plate)

• The area of contact is 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 creates a junction called the neuromuscular junction

• At the neuromuscular junction, the neurilemma becomes continuous with the sarcolemma

• The muscle membrane thickens to form the motor end plate

• The muscle membrane under the sole feet invaginates to enclose them and is called the synaptic gutter

Synaptic Cleft and Subneural Clefts

• The space between the sole feet and the muscle fiber membrane is called the synaptic cleft or synaptic space, which is 25 nM wide
• At the bottom of the gutter are numerous smaller folds of the muscle membrane called subneural clefts which increases the surface area for synaptic transmitter action

Acetylcholine

• The sole foot contains many vesicles filled with acetylcholine (Ach) and mitochondria for its synthesis
• Synapsin proteins 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 located to each side of each dense bar

Acetylcholinesterase

• Large quantities are present at the border of the gutter, which hydrolyzes Ach
• It destroys Ach within a few milliseconds after its release from synaptic vesicles
• The short time that 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
• Acetate escapes to the blood stream
• The rapid removal of Ach prevents continued muscle re-excitation

Miniature End Plate Potential (MEPP)

• A state of persistent localized subthreshold DP (0.5 mV in amplitude) of the muscle fibers at the MEP during rest
• This does not reach the firing level, so it does not lead to an AP
• Caused by continuous release of small amounts of Ach due to continuous rupture of a few vesicles that contain a chemical transmitter, at the nerve terminals

Mechanism of Neuromuscular Transmission

• Action potential travels in the motor neuron
• Which opens voltage-gated Ca++ channels in terminal buttons
• Ca++ influx
• Phosphorylates synapsin proteins that anchor the Ach vesicles to the cytoskeleton of the presynaptic terminal
• This frees the Ach vesicles from the cytoskeleton and allows them to move to the active zone of the presynaptic neural membrane, adjacent to the dense bars
• Vesicles dock at release sites and fuse with the neural membrane
• Results in vesicles emptying the content of Acetylcholine (Ach) into the synaptic space by 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
• This leads to open Na+ and K+ channels (ligand-gated)
• More Na+ than K+ diffuses
• End plate potential development
• When EPP reaches the firing level, an AP is generated
• Ach then detaches from receptors
• Ach then diffuses into folds of MEP
• Ach is rapidly hydrolyzed by cholinesterase, prevents the re-excitation of the muscle

End Plate Potential (EPP)

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

Properties of Neuromuscular Transmission

• Unidirectional: the impulse is allowed to pass from the nerve to the muscle
• Transmission of impulses at the MEP is delayed by 0.5 mS
• The delay is needed for: release of Ach, diffusion through the synaptic cleft, combination with receptors, and sodium (Na+) influx until the firing level is reached
• Easily fatigued by repeated stimulation, mostly due to exhaustion of Ach
• Affected by ions:
• Excess Ca++ increases Ach release which increases transmission due to rupture of Ach vesicles
• Excess Mg++ decreases Ach release which decreases transmission due to blocking vesicle rupture
• Affected by drugs:

Drugs that Stimulate Neuromuscular Transmission

• Acetylcholine-like action with drugs that are not rapidly hydrolyzed by cholinesterase enzyme, such as methacholine and carbachol
• Drugs preserve the liberated Ach at the MEP by inactivating acetylcholinesterase such as neostigmine and physostigmine (eserine)

Drugs that Block Neuromuscular Transmission

• Curare (tubocurarine) and some other related drugs (e.g. Flaxedil) block Ach action by occupying its receptors at MEP in competitive inhibition
• These are used as muscle relaxants during surgical operations
• Curare was used by Red Indians to paralyze their victims
• In large doses it may be fatal due to paralysis of the respiratory muscles
• Botulinum toxin inhibits the release of Ach
• Clostridium botulinum is a specific bacteria that causes potent botulinum toxins
• These act by preventing neurotransmitter release in the CNS and at the neuromuscular junction, causing flaccid paralysis
• Botulism comes from ingestion of contaminated food or wound infection
• Hemicholinium blocks the reuptake of choline into nerve terminals, thereby depleting stores of Ach

Examples of diseases and drugs that affect the neuromuscular junction

• Methacholine & carbachol stimulate Neuromuscular Transmission by Acetylcholine-Like Action
• Curare blocks nicotinic receptors at MEP and therefore blocks the Binding of acetylcholine To receptors
• Myasthenia gravis destroys Ach receptors
• Eserine and prostagmine (a drug) Inhibit affect acetylcholinesterase

Myasthenia Gravis

• It is a hereditary disease that affects females more than males
• Characterized by marked progressive weakness and easy fatigability of muscles
• It is caused by formation of autoantibodies (autoimmune) causing destruction of Ach receptors at the MEP which decreases the response to Ach
• It is treated by drugs which inhibit cholinestrase e.g. prostagmine which preserves Ach for better neuromuscular transmission and prolongs the action of ACh at the MEP
• Eserine is NOT used in the treatment because it produces dangerous parasympathetic effects e.g. hypotension due to V.D. and bradycardia
• Additional effects include excessive salivation, defecation and micturition
• The antagonist of eserine is atropine and the antagonist of atropine is either Ach or eserine

Lambert-Eaton Syndrome

• A neuromuscular disease with symptoms of progressive muscle weakness and fatigue
• Cause: circulating antibodies to presynaptic Ca2+ channels, prevents calcium entry into nerve terminals preventing DP and release of Ach

Summary

• Neuromuscular junction is the area of contact between the nerve fiber and the muscle fiber
• At the border of the gutter, there is a large quantities of the enzyme cholinesterase which hydrolyzes Ach
• Properties of neuromuscular transmission include Unidirectional, delayed and fatigued
• Neuromuscular Transmission also affected by ions and drugs
• Myasthenia gravis is a hereditary disease due to the formation of autoantibodies (autoimmune)