ACh 2 Flashcards

1
Q

Curare

A

• 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

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2
Q

NMJ blockers (NMBs)

A

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.

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3
Q

Non-depolarising NMB agents

A

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.

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4
Q

What (partly) reverses effect of NMBs?

A

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

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5
Q

Depolarising NMB agents

A

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!

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6
Q

Neuromuscular junction

A

Diagram

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7
Q

Neuromuscular junction and embryogenesis

A
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.
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8
Q

Neuromuscular junction pathology

A

• 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

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9
Q

Discovery of myasthenia gravis

A

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

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10
Q

Myasthenia gravis

A

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

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11
Q

myasthenia gravis and nicotinic receptors

A
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.
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12
Q

Myasthenia gravis: autoantibodies

A

Diagram

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13
Q

Myasthenia gravis: treatment

A

• 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

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14
Q

Congenital myasthenic syndromes

A

• 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

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15
Q

Congenital myasthenic syndromes

Types

A

Table

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16
Q

Endplate AChE deficiency

A

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.

17
Q

Primary AChR deficiency

A
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.
18
Q

Slow channel syndrome

A

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

19
Q

Fast channel syndrome

A

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

20
Q

Treatment of congenital myasthenic disorders

A

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

21
Q

ACh and cognition

A

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.

22
Q

Wired transmission

A

Conventional Synapse Point-to-point

23
Q

Volume transmission

A

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