Acetylcholine ☺️ Flashcards
Synthesis
Choline (diet+ recycled) + ACoA (Krebs) =(choline acetyl transferase)=> ACh
ChaT synthesised in cell body, transported to terminals for ACh synthesis
Storage
-describe how the relative concs differ intravesicularly and intracellularly
Vesicular ACh transporter (ACh 2H exchanger)
- intravesicular [100mM]
- intracellular [1mM]
Describe how ACh is released
-what drug is clinically useful
Ca dependent
-intracellular [Ca] increases => fusion of vesicle with membrane => ACh release
Botulinum toxins (muscle spasm treatment)
Name the 2 types of receptor that respond to ACh
- what drugs are clinically useful
- when would you use them
Pentameric nicotinic ligand gated ion channels
Full agonists => nicotine (NRT), suxamethonium (prolongs depolarisation => muscle relaxant)
Partial agonists => varenecline (smoking cessation)
Reversible antagonist => pancronium, vercuronium (opposes depolarisation => muscle relaxant)
Muscarinic GPCRs
Reversible antagonists => atropine (variety of uses), ipratropium (SAMA), procyclidine (Parkinsonism)
Describe the degradation and reuptake of ACh
-what drugs are clinically useful
ACh =(acetylcholine transferase)=> choline + acetic acid
-occurs in synaptic cleft
Neostigmine, physostigmine, galantamine, rivastigmine => myasthenia gravis (prolongs ACh life)
Choline transporter absorbed by presynaptic membrane
Describe 3 recreational drugs that also affect the ACh pathway
- how do they work
- do they have medical uses?
Nicotine => nicotininc receptor agonist
-NRT
Scopolamine/hycoscine => inhibit ACh function
-motion sickness, postop N+V
Henbane => hallucinogenic
How is ACh implicated in
- dementia
- myasthenia gravis
- Parkinsons
- motion sickness
- analgesia
Dementia => loss of cholinergic neurones affecting learning and memory
Myasthenia gravis => loss of post synaptic ACh receptors at NMJ
Parkinsons => cholinergics used to relieve constipation
Motion sickness => ACh diffuses into CSF in 4th ventricle and activates receptors in autonomic and emetic centers
Analgesia => ACh may help with pain relief
Where is ACh released from
Where are the receptors
Basal forebrain, midbrain => all brain regions
Nicotininc - Lower motor neurones at NMJ, post ganglionic ANS
Muscarininc - PNS (heart, vessels), SNS (sweats)
What are the neurological changes that occur in dementia
ACh system is affected first but other systems are lost as dementia progresses
- fewer neurotubules bringing vesicles down
- fewer mitochondria, vesicles and NTs
Cortex shrivels => loss of grey matter, wider sulci, narrow gyri
Ventricles enlarge
Hippocampus shrinks => reduced ability to form new memories
What are some structural changes that occur at the NMJ that may result from muscle changes
Decreased
- nerve terminals (hard to replace them)
- post synaptic folds
- synaptic vesicles
- NTs
- mitochondria
- satellite cell proliferation (used to be v abundant at NMJ)
Increased
- fusion events in mitochondria (due to increased ROS)
- quantal content (vesicles contain increased NT in an attempt to restore the loss)
What are some functional changes that occur at the NMJ that may result from muscle changes
Increased
- excitation contraction uncoupling so contraction is less efficient (uncoupling of RyRs on Ttubules to voltage sensing DHPRs on SR)
- impaired activation of muscle agonists
Decreased
- repair capacity by Schwann cells
- Ca release
- reinnervation capacity
Describe how the early signs of Parkinsons and Lewy body dementias can manifest
How might you manage this
Lewy bodies form in dopaminergic and cholinergic neurones
Lewy bodies also found in myenteric plexus in ENS => decreased rate of gastric emptying => constipation
-ENS innervated by vagus, prevertebral ganglia
Patch rivastigmine => decreased discomfort from constipation, increasd DOPA drug absorption
