Session 6: The skeletal muscle neuromuscular junction- physiology and pathophysiology Flashcards
Describe the basic organisation of the neuron pathways that control the movement of voluntary muscle.
- Motor pathways originate in the cerebral cortex
where groups of neurons, organised into vertical
columns, control the contraction of individual skeletal
muscles. It controls all voluntary movements - Betz cells are the beginning of the pyramidal
(corticospinal) tracts, the major pathways of the body - 80 to 85% of the fibres cross at the level of the
medulla oblongata (pyramids) to the contralateral
side and form the lateral corticospinal tract - upper motor neurons: from the primary motor cortex
to the spinal cord - lower motor neurons: from the anterior (ventral) horn
of the spinal cord to specific skeletal muscles
Identify the location in the spinal cord of the cell bodies of the axons of the axons innervating skeletal muscles.
Anterior grey matter horn of the spinal cord
Identify the two main categories of cholinergic receptors, with their respective locations and compare the speed and duration of their associated effects.
- Nicotinic cholinergic receptors:
- found in autonomic ganglia and at the skeletal muscle
neuromuscular junctions
- rapid and brief effect - Muscarinic cholinergic receptors:
- effector cells that are stimulated by the postganglionic
cholinergic neurons of either the parasympathetic
nervous system or the sympathetic system
- effect is slower to commence and has a longer
duration
Draw and describe the structure of a typical skeletal muscle neuromuscular junction.
Check drawing in notebook.
Explain the terms “subneural cleft”, “neuromuscular junction”, “motor endplate”, “endplate potential” and “miniature endplate potential”.
Subneural cleft- smaller folds of the muscle membrane which greatly increase the surface area at which the synaptic transmitter can act
Neuromuscular junction- junction each nerve ending makes with the muscle fiber near its midpoint
Motor endplate: the entire structure of a nerve fiber which forms branching nerve terminals that that invaginate into the surface of the muscle fiber but lie outside the muscle fiber plasma
Endplate: a local positive potential change inside the muscle fiber membrane created by the opening of Ach-gated channels to allow large numbers of sodium ions to pour to the inside of the fiber
Miniature endplate potential: a tiny depolarising subthreshold potential present at rest, due to small quanta of Ach being randomly released (at rest)
Describe acetylcholine synthesis, storage and secretion (including the role of the voltage-gated calcium ion channels”.
Synthesis: it is synthesised in the terminal endings and varicosities of the cholinergic nerve fibers, where it is stored in vesicles in highly concentrated form until it is released. the basic chemical reaction of this synthesis is :
Acetyl-CoA + Choline -> Acetylcholine
Once acetylcholine is secreted into a tissue by a cholinergic nerve ending, it persists in the tissue for a few seconds while it performs its nerve signal transmitter function
Briefly describe the action of acetylcholine on the postsynaptic ion channels, including the passage of various ions.
After acetylcholine has become attached and a conformational change has opened the channel, sodium ions enter the muscle fiber. Negative charges at the channel mouth prevent the passage of negative ions such as chloride ions.
Relate the amount of acetyl choline on the postsynaptic ion channels, including the passage of various ions.
Ordinarily, each impulse that arrives at the neuromuscular junction causes about three times as much end plate potential as that required to stimulate the muscle fiber. Therefore, the normal neuromuscular junction is said to have a high safety factor.
However, stimulation of the nerve fiber at rates greater than 100 times per second for several minutes often diminishes the number of acetylcholine vesicles so much that impulses fail to pass into the muscle fiber. This situation is called fatigue of the neuromuscular junction.
Explain how an endplate potential (EPP) initiates an action potential.
If an endplate is strong enough, it can cause enough sodium channels to open so that the self-regenerative effect of more and more sodium ions flowing to the interior of the fiber initiates an action potential.
Briefly describe the basic pathophysiological mechanism (which includes whether it is a depolarising or a non-depolarising mechanism) by which each of the following clinical conditions disrupts skeletal muscle neuromuscular transmission and indicate the anatomic level of signal transfer disruption:
- motor neuron denervation/demyelination
- myasthenia gravis
- Lambert-Eaton myasthenic syndrome
- poliomyelitis
- slow channel syndrome (which is congenital)
- botulinism (Clostridium botulinum toxin)
- female black widow spider envenomation
- organophosphate and carbamate poisoning (which
initially has a depolarising effect)
- Clostridium tetani (tetanus) toxin
Motor neuron denervation/demyelination:
Thiamine deficiency can cause degeneration of the nerve fibers myelin sheath in the nervous system. Lesions in the peripheral nerves cause irritability, resulting in “polyneuritis”. Fiber tract degeneration can occasionally lead to paralysis, the muscles atrophy, resulting in severe weakness .If denervation occurs, the innervated organ becomes more sensitive to acetylcholine.
Myasthenia gravis:
- More common autoimmune disorder where
autoantibodies damage the nicotinic cholinergic
receptors and patients present with muscle
weakness
- Edrophonium hydrochloride leads to rapid symptom
improvement
- Findings are restricted to the motor system.
Lambert -Eaton:
- Less common autoimmune disorder of neuromuscular
transmission
- Repetitive nerve stimulation leads to facilitation of the
muscle action potential
- Weak muscles become stronger with exercise
- Results from impaired acetylcholine release when
auto-antibodies react with and block the presynaptic
voltage-gated calcium ion channels
Poliomyelitis:
- Motor neuron abnormality
Slow channel syndrome:
- Congenital disorder
Botulism:
- Exotoxin interferes w/ sufficient acetylcholine release
at the NMJ
- ANS is involved
- May cause death due to respiratory paralysis
Female black widow spider envenomation:
- Common presynaptic disorder where there is
autonomic instability due to Ach release
- Results in hypertension
Organophosphate and carbamate poisoning:
- Toxin
- Leads to muscarinic effects
- Depolarising effect
Clostridium tetani (tetanus) toxin: - Toxin
Identify and classify two classes of drugs that influence skeletal muscle neuromuscular signal transmission, by referring to their indications and mechanisms of action.
1. Depolarising skeletal muscle relaxants (structural acetylcholine analogues): Only SUCCINYL(DI)CHOLINE which is structurally similar to two acetylcholine molecules and can therefore act as an antagonist at the nicotinic cholinergic receptors of the neuromuscular junction. It is used in theatre to facilitate the intubation of patients.
- Non-depolarising skeletal muscle relaxants (competitive cholinergic receptor antagonists):
For example, curariform drugs such as d-tubacurarine and pancuronium. These drugs result in the released acetylcholine being unable to interact with the nicotinic cholinergic receptor. They are used for surgical procedures (to maintain muscle relaxation for variable periods).
Identify characteristic symptoms and signs of skeletal muscle neuromuscular junction dysfunction.
Neuromuscular junction disorders produce pure motor syndromes that predominantly affect cranial nerve-supplied muscles, particularly the ocular muscles
Muscle fatigue and fluctuation in strength are important clues to nerve-skeletal muscle junction dysfunction.
