ACh 2

Question 1

Curare

Answer 1

• Muscle nAChRs are selectively
blocked by curare (arrow poison) • Curare is a competitive antagonist
of ACh • When bound to receptor, curare
elicits no response • Antidote: acetylcholinesterase
inhibitor

Question 2

NMJ blockers (NMBs)

Answer 2

Cause paralysis of skeletal muscles. • Can work presynaptically (e.g. botulinum
toxin) or postsynaptically (those used clinically). • Widely used clinically in conjunction with anaesthesia to
prevent muscle movement during surgery (only when artificial
ventilation is available!), but they have no sedative or analgesic
effects. • Two types: non-depolarising and depolarising NMB agents.

Question 3

Non-depolarising NMB agents

Answer 3

Non-depolarising blocking agents competitively block the
binding of ACh to the nAChRs (e.g. tubocurarine, rocuronium). • Majority of clinically-used NMB agents. • Usually poorly absorbed and rapidly excreted, so given IV.

Question 4

What (partly) reverses effect of NMBs?

Answer 4

administration of
neostigmine (anticholinesterase) post- operatively, but requires addition of atropine (glycopyrronium) to block unwanted muscarinic effects.

Question 5

Depolarising NMB agents

Answer 5

depolarising the motor end plate. • Produce transient twitching of skeletal muscle “fasciculation”
before neuromuscular block. • Succinylcholine (suxamethonium) is the only one used
clinically. • Fast onset (30 s) / offset (5-10 min). • Side effects include bradycardia, hyperkalaemia, malignant
hyperthermia – 65% mortality rate!

Question 6

Neuromuscular junction

Answer 6

Diagram

Question 7

Neuromuscular junction and embryogenesis

Answer 7

Agrin:
• During embryogenesis,
agrin initiates formation
of NMJ, in the presence
of MuSK and Lrp4. • This is key for AChR
clustering (together with
Rapsyn) and fold
formation.
• In adults, it regulates the
maintenance and regeneration of
density lipoprotein receptor-related protein 4
postsynaptic NMJ.

Question 8

Neuromuscular junction pathology

Answer 8

• Autoinmune disorders:
o Myasthenia gravis: autoantibodies against AChRs
o Neonatal myasthenia gravis: when maternal anti-AChRs antibodies transferred to foetus o Neuromyotonia (Isaac’s syndrome): hyperexcitation of motor nerves
• Genetic disorders:
o Congenital myasthenic syndromes: mutations in
presynaptic, synaptic and postsynaptic proteins

Question 9

Discovery of myasthenia gravis

Answer 9

Jon Lindstrom 1970s
generated antibodies to purified ACh receptor; inject reference with these antibodies causes muscle weakness similar to patients with MG; autoimmune theory confirmed with later patients studies

Question 10

Myasthenia gravis

Answer 10

Autoinmune disorder, caused by antibodies targeting the neuromuscular
junction. • Symptoms: muscular weakness and
fatigability • Usually affects ocular (ptosis), bulbar
(mouth and throat) and proximal extremity muscles. • Prevalence: 150-300 per 1,000,000
individuals

Question 11

myasthenia gravis and nicotinic receptors

Answer 11

Loss of nAChRs coupled
with reduction in
junctional folds and
enlargement of synaptic
cleft. • Repetitive muscle
stimulation leads to
progressively decreasing
MUSCLE (not nerve)
action potentials, with
decreasing muscle power.

Question 12

Myasthenia gravis: autoantibodies

Answer 12

Diagram

Question 13

Myasthenia gravis: treatment

Answer 13

• Symptomatic drug therapy:
o AChE inhibitors (e.g. pyridostigmine, neostigmine)
o Drugs that increase ACh presynaptic release (e.g.
3,4-diaminopyridine (blocks pre-syn. K channels))
• Immunosuppressive drug therapy
• Thymectomy

Question 14

Congenital myasthenic syndromes

Answer 14

• Group of inherited disorders caused by mutations in
genes encoding for proteins essential for maintaining
the integrity of neuromuscular transmission.
• At least 20 different genes known to cause CMS, most confined to NMJ but some ubiquitously expressed.
• Principal clinical feature: fatigable weakness
• UK prevalence: 9.2 cases per million children under 18

Question 15

Congenital myasthenic syndromes

Types

Answer 15

Table

Question 16

Endplate AChE deficiency

Answer 16

Endplate AChE deficiency due to COLQ mutations: • COLQ gene encodes for the triple-
stranded collagenic tail anchoring AChE
to the synaptic basal lamina • COLQ mutations result in prolonged
synaptic currents and action potentials
because of extended residence of Ach
in the synaptic space. • Weakness can affect all voluntary
muscles.

Question 17

Primary AChR deficiency

Answer 17

Can result from mutations
in any of the nAChR
subunits, but most occur in
the ε subunit
• Patients with heterozygous
or homozygous low-
expressor mutations in the
non-ε subunits are severely
affected and have high
mortality in infancy or early
childhood.

Question 18

Slow channel syndrome

Answer 18

Caused by dominant mutations in
the ligand-binding or pore domains
of the nAChR. • Presents in children. • There is severe involvement of the
cervical, scapular and dorsal forearm muscles.
Longer duration opening of the ACh receptor channel and slower endplate current decay

Question 19

Fast channel syndrome

Answer 19

Caused by a recessive mutation in
one allele of a nAChR subunit. • No clinical clues point to the
diagnosis of a fast-channel
syndrome; in vitro microelectrode
studies are required. • There is decreased probability
that the AChR is opened by
physiological concentrations of
ACh.
Brief openings of ACh receptor channel and accelerated endplate current decay

Question 20

Treatment of congenital myasthenic disorders

Answer 20

Cholinergic “agonists”:
o Pyridostigmine: AChE inhibitor
o Neostigmine
o Amifampridine (3,4 DAP): increases ACh release
• Long-lived open-channel blockers of the AChR ion channel
(fluoxetine, quinidine).
• Adrenergic agonists (salbutamol, ephedrine).
A molecular diagnosis is essential to inform the choice of therapy

Question 21

ACh and cognition

Answer 21

Old studies showed that muscarinic receptor antagonists (e.g. atropine) impair cognitive
abilities in humans and animals.
• Further evidence demonstrated a role of
cortical cholinergic input system in attention
and memory encoding.

Question 22

Wired transmission

Answer 22

Conventional Synapse Point-to-point

Question 23

Volume transmission

Answer 23

Paracrine release, “en-passant” ; can still include presynaptic action