ACh 2 Flashcards
Curare
• 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
NMJ blockers (NMBs)
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.
Non-depolarising NMB agents
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.
What (partly) reverses effect of NMBs?
administration of
neostigmine (anticholinesterase) post- operatively, but requires addition of atropine (glycopyrronium) to block unwanted muscarinic effects.
Depolarising NMB agents
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!
Neuromuscular junction
Diagram
Neuromuscular junction and embryogenesis
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.
Neuromuscular junction pathology
• 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
Discovery of myasthenia gravis
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
Myasthenia gravis
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
myasthenia gravis and nicotinic receptors
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.
Myasthenia gravis: autoantibodies
Diagram
Myasthenia gravis: treatment
• 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
Congenital myasthenic syndromes
• 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
Congenital myasthenic syndromes
Types
Table
Endplate AChE deficiency
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.
Primary AChR deficiency
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.
Slow channel syndrome
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
Fast channel syndrome
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
Treatment of congenital myasthenic disorders
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
ACh and cognition
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.
Wired transmission
Conventional Synapse Point-to-point
Volume transmission
Paracrine release, “en-passant” ; can still include presynaptic action
