Neuromuscular Junction Flashcards
Tell me about the ANS and what it regulates?
- Regulates activity of:
Smooth muscles
Exocrine glands (some endocrine glands)
Cardiac tissue
Metabolic activities
- Involuntary
- Regulates by brain stem centres
Tell me about the somatic NS
- Activates skeletal muscle contraction
- Voluntary body movements
- Regulated by corticospinal tracts + spinal reflfexes
Tell me about exocrine and endocrine secretion i.e. what it goes through and to where?
exocrine- section into external environment through ducts, e.g. (sweat, oil, wax, enzymes, etc)
endocrine- secretion into internal environment with no ducts and hormones secreted
Receptors/ agonists present in the sympathetic, parasympathetic and somatic nervous system
What does the somatic NS not have a relay neuron between?
The cell body and muscle receptor
Acetylcholine synthesis and degradation
Tell me the types of nicotinic receptors?
Where are they located?
N1 or NM and N2 or NN
type 1 sits in muscle and type 2 in neuron
Ligand-gated ion channels
How many acetylcholine molecules do nicotinic receptors require to bind?
What is the structure of the nicotinic receptors?
- Required binding of two acetylcholine molecules
- Composed of five subunits (pentamer)
- Five different types of subunits
- Alpha, beta, gamma, delta and epsilon
- 10 different alpha and 4 different beta subunits
- NM receptors contain only alpha1 and beta1 subtypes plus delta and gamma/epsilon
- NN receptors contain alpha2-10 and beta2-4 subtypes
When was the AA sequence for the nicotinic receptor determined?
The amino acid sequence for the nicotinic receptor was determined after solubilization of the receptor from the electric organ of Torpedo californica using anionic detergents such as sodium dodecyl sulfate, passing the receptor through an affinity column containing a bungarotoxin (from snake venom) and washing the receptor from the column. Subsequently, molecular biological techniques were used to clone additional receptor subunits. The nicotinic receptor consists of five polypeptide subunits. The amino acid sequence for the a subunits consists of a glycolipid region (which contains the ACh binding site and a sulfhydryl groups) with four hydrophobic regions that span the membrane. Nine a subunits have been cloned, along with four b subunits. In the neuromuscular junction, d and g subunits also have been identified. The g subunit is replaced by an e subunit in the adult muscle.
ACh and receptor
What is the neuromuscular junction?
a specialised form of synaptic transmission: communication between neurons and skeletal muscle
Tell me the steps to the major events that occur in NMJ transmission?
Major events in NMJ transmission
- Motor neuron depolarization causes action potential to travel down the nerve fiber to the neuromuscular junction
- Depolarization of the axon terminal causes an influx of Ca2+
- which triggers fusion of the synaptic vesicles and release of neurotransmitter (Acetylcholine; ACh) by exocytosis
- ACh diffuses across the synaptic cleft and binds to post-synaptic ACh receptor (AChR) located on the muscle fiber at the motor endplate (ligand gated cation channels is the receptor)
- Binding of ACh to AChRs opens the channels causing an influx of Na+ (K+ flux out)
- depolarization of the sarcolemma that travels down the t-tubules and ultimately causes the release of Ca2+ from the sarcoplasmic reticulum - CONTRACTION.
- How Ach is removed: Unbound ACh in synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChE) to acetic acid and choline (choline put back in terminal for the resynthesis of acetylcholine)
Tell me some NMJ disorders?
- Myasthenia gravis
- Lambert-Eaton myasthenic syndrome
- Neuromyotonia (Isaac’s syndrome)
Tell me about myasthenia gravis
- “grave muscle weakness”
- Autoantibodies to the nicotinic AChR on the motor end-plates of muscles.
- Binding of ACh is blocked and muscle activation is inhibited.
- The autoantibodies also induce complement-mediated degradation of the AChRs, resulting in progressive weakening of the skeletal muscles.
- Autoantibodies to MuSK, which is important for the tight clustering of AChRs at the neuromuscular junction .
Tell me the symptoms to the NMJ disorder myasthenia gravis
Tell me about the NMJ disorder Lambert-Eaton myasthenic syndrome
- Autoantibodies to presynaptic voltage-gated calcium channel (VGCC)
- These antibodies interfere with the calcium-dependent release of ACh from the presynaptic membrane and subsequently cause a reduced endplate potential on the postsynaptic membrane, resulting in NMJ transmission failure.
Tell me about the NMJ disorder Neuromyotonia (Isaac’s syndrome)
- Autoantibodies to presynaptic voltage-gated potassium channel (VGKC)
- Autoimmune neuromyotonia is typically caused by antibodies that bind to potassium channels on the motor nerve resulting in continuous/hyper-excitability.
What is the neurotransmitter always used as the NMJ?
Acetylcholine
A client with myasthenia gravis asks the nurse why the disease has occurred. The nurse bases the reply on the knowledge that there is…?
A decreased number of functioning acetylcholine receptor sites
Katrina a client with myasthenia gravis is to receive immunosuppressive therapy. The nurse understands that this therapy is effective because it…?
Decreases the production of autoantibodies that attack the Ach receptors
Drugs working on NMJ
NM blocking drugs
NMJ blocking reversing agents
Tell me the following about cholinesterase inhibitors…
- What do they increase the availability of?
- What do they cause the reverse of?
- It is the first line for?
- What do they inhibit?
- Increase the availability of acetylcholine (ACh), partially overcome the decreased receptor availability
- Reverse non-depolarizing muscle blockade
- First line for ocular myasthenia
- They inhibit the acetylcholinesterase enzyme from breaking down Ach, thereby increasing the level and duration of action of neurotransmitter acetylcholine
The structure of Organophosphate insecticides (parathion)…
What are organophosphates?
Organophosphates are irreversible AChE inhibitors
DIFP: diisopropyl fluorophosphate
Tell me the following about Edrophonium…
- chemical name
- trade names
- what it is
- what it in competition with
- uses
- N-ethyl-3-hydroxy-N,N-dimethylbenzenaminium
- Trade names Tensilon, Enlon and Reversol.
- Edrophonium is a readily reversible AChE inhibitor that prevents breakdown of ACh
- True competitive inhibition of AChE at the NMJ
- Rapid dissociation
- Used in diagnosis myasthenia gravis
- Tensilon test: differentiate myasthenic crisis from cholinergic crisis
- myasthenic crisis: not enough neuromuscular stimulation: Edrophonium will reduce the muscle weakness by effectively supplying more ACh
The next image is an example of a cholinergic crisis…
too much neuromuscular stimulation: Edrophonium will make the muscle weakness worse by inducing a depolarizing block
What is physostigmine?
What is it aka?
Clinical uses
- also known as eserine from éséré, Calabar bean: witchcraft
- Reversible pseudo-competitive AChE inhibitor
Clinical uses
- Physostigmine is used to treat myasthenia gravis, glaucoma, Alzheimer’s disease and delayed gastic emptying.
- It can cross the blood brain barrier and can be used to treat effects of atropine and other anticholinergic drug overdoses
Antispasmodics
Tell me the symptoms of botulism (food-borne botulism, wound botulism and infant botulism)
- Double vision
- Blurred vision
- Droopy eyelids
- Slurred speech
- Difficult swallowing
- Dry mouth
- Muscle weakness (starts in shoulders and descends through body)
Botox uses for both medical and cosmetic reason
