Acetylcholine Flashcards
How is acetylcholine synthesised?
(3 marks)
- Formed from choline and acetyl coenzyme A (acetyl CoA)
- Catalysed by choline acetyltransferase (ChAT)
choline acetyltransferase
- choline + acetyl CoA ⇔acetylcholine + CoA
What can happen if you block cholinergic activity?
Can cause muscular paralysis
Where is ChAT found?
In cholinergic neurons and is released as ACh
How can you experimentally identify cholinergic neurons?
Stain fo ChAT
What is the rate of ACh controlled by?
(2 marks)
Availability of precursors and rate of cell firing
Direct correlation between levels of ChAT and ACh
How is ACh released?
(3 marks)
- ACh is stored in vesicles and moves inot vesicles by vesicular ACh transporters (VAChT)
- VAChT is blocked by drug vesamicol which may reduce amount of ACh in vesicles to be released when neurons fire
- But ACh in cytoplasm increases as it doesn’t affect rate of ACh synthesis
What is botulinum?
Toxin that inhbits ACh release - can grow anaerobically and can be present in out of date canned food
Outline the mechanism of Botulinum
- Inhibits ACh release at neuromuscular junction by preventnig fusion of synaptic vesicles w/ nerve terminal membrane
What are some of the dangerous effects of botulinum?
(2 marks)
- Muscle paralysis
- Produced by anaerobic bacterium Clostridium botulinura
What are some of the benefits of botulinum?
(3 marks)
- Can be used to treat disorders characterised by involuntary muscle contractions
- Used by dermatologists as ‘Botox’:
- treats facial wrinkles as it casuses localised paralysis and reduces wrinkles for a few months
How is ACh inactivated?
(3 marks)
- Acetylcholinesterase enzyme (AChE) degrades it post-synaptically into choline and acetic acid
- AChE in presynaptic cells can metabolise excess ACh that may have been synthesised
- AChE located on post synaptic membrane
What happens to choline after it has been reduced?
- Considered biologically inactive and can be recycled and brought back to presynaptic region by choline transporter
What drugs block the choline transporter and what is seen in mutant mice with no choilne transporter at birth?
(3 marks)
- Hemicholinium-3 (HC-3) - blocks it and reduces ACh production
- Mutant mice - will die an hour after birth
- Lack of ACh synthesis and release at NT junctions causes breathing difficulties
Does ACh bind to metabotropic or ionotropic receptors?
Both x
How and what drugs prevent the activation of ACh?
(4 marks)
- Done by blocking AChE
- Physoltigmine - crosses blood brain barrier and affects CNS
- Neostigmine and pyridostigmine - synthetic analogues of physotigmine that DO NOT cross blood brain barrier
- ^^^ reversible AChE inhibitors
What can some varities of ‘nerve gas’ do?
- Cause ACh accumulation and overstimulation of cholinergic synapses, throughout CNS and PNS causing msucle paralysis and death by asphyxiation
Where is ACh present in the sympathetic and parasympathetic nervous system respectively?
(2 marks)
- Sympathetic: ACh present only preganglionically (uses NE from ganglion to target)
- Parasympathetic: ACh present only in preganglionically and on target organ
How many regions does ACh provide cholinergic innervation to in the brain?
8 x
What kind of drugs are prescribed in the early stages of PD?
(2 marks)
Anticholinergic drugs - as need balance of DA and ACh
e.g. Benztropine mesylate
Where do the cholinergic neurons found in the nucleus basalis project to?
Rostrally to neocortex and invovled in positive effect of ACh
What is the basal forebrain cholinergic system and what does 192 IgG do to it?
(5 marks)
- Origin of cholinergic innervation of cerebral cortex, hippocampus and other limbic structures
- Uses selective neurotoxin 192 IgG - saporin:
- 192 IgG monoclonal antibody binds specifically to surface protein on basal forebrain cholinergic neurons
- When injected into BFCS, cholinergic interneurons take up the toxin
- Causes those neurons to be destroyed and neighbouring non-cholinergic cells are spared
What do the cholinergic neurons in the dorsal lateral pons influence?
(2 marks)
- Excitatory influence on midbrain DA neuron firing
- Mediated by post synaptic nicotinic cholinergic receptor
What are the two types of cholinergic receptor?
(2 marks)
Nicotinic receptor: agonist is nicotine - an alkaloid (found on muscle cells at neuromuscular junction)
Muscarinic receptor - respond to muscarine - an alkaloid (some inhibit cAMP and stimulate K+)
What do nicotinic receptors do?
(3 marks)
- Ionotropic
- ACh binds and channel opens Na+ and Ca2+ flood into neuron or muscle cell and membrane is depolarised
- Nicotinic receptors mediate post excitatory responses in both CNS and PNS
What characteristics do all nicotinic receptors have in common?
(3 marks)
- 5 subunits: α β γ δ ε (subunits may change don’t know exact number of receptors)
- 10 α subunits and 4 β subunits
- Receptors in muscle cells have diferent composition than the ones in neurons
What are the 3 types of nicotinic receptor?
- Muscle nicotinic receptor
- Neuronal α4β2 receptor
- Neuronal α receptor
What happens when nicotinic receptors are subject to continuous agonist exposure?
(5 marks)
- Become desensitised - channel remains closed despite agonist presence
- After short time spontaneously resensitize and able to respond to agonist
- Not all recpetors are desensitized, but produce persistant depolarisation of cell membrane
- After long exposure to agonist depolarisation block occurs
- Resting potential of membrane lost and cell can’t be excited until agonist removed and membrane repolarised
Give an example of a nicotinic ACh receptor agonist.
(2 marks)
- Succinlycholine:
- Muscle relaxant: reistant to breakdown by AChE - stimulate nicotinic receptor induces depolarisation block
Give an example of some antagonists to the nicotinic receptor.
(4 marks)
-
Mecamylamine -
- antagonist that blocks nicotinic receptors both in CNS and a_utonomic ganglia_
-
D-turbocarcarine -
- antagonist of muscle nictonic receptor and main ingredient of curare
How many muscarinic receptors are there?
5 - all metabotropic tht operate via secondary messengers
What does the activtation of muscarinic M3 cells stimulate the secretion of?
Secretion of insulin by β-cells
Where are M5 receptors located and what do they do?
(3 marks)
- Hippocampus, hypothalamus and midbrain DA areas:
- contribute to excitatory effect on dopamine neurons mediated by nicotinic receptors
- Involced in rewarding and dependence producing effects of abused drugs
What can be seen in M5 receptor KO in mice and what does this suggest?
(2 marks)
- Shows deficits in morphine and cocaine reward system
- Suggest M5 receptor important in regulating drug abuse which doesn’t directly regulate the cholinergic system
Where are peripheral muscarinic receptors located and what are they activated by?
(2 marks)
- Cardiac muscle, smooth muscle and insulin secreting cells of the pancreas
- Activated by ACh released from post ganglionic fibres of the parasympathetic NS
Where is M2 receptor located and what does it do?
(2 marks)
- In cardiac muscle - a peripheral receptor
- Stimulation of parasympathetic NS slows HR and decreases contraction strength
Where is M3 receptor found and what does it do?
(3 marks)
- Smooth muscle (peripheral m receptor)
- Activation causes contraction
- Receptors mediate secretory responses of ANS e.g. lamination and salivation
What are some of the muscarinic receptor agonists and what can high doses cause?
(5 marks)
- Muscarine
- Pilocarpine
- Arecoline
- Exaggerated parasympathetic responses
- Cardiovascular collapse, convulsions, coma and death
What is atropine?
(2 marks)
- Antagonist of muscarinic receptors
- Dilates pupils and reduces secretions that clog airways and counteract poisoning by choinergic agonists
What is scopolamine and what does it do?
(3 marks)
- Antagonist for muscarinic receptors
- Therapeutic doses: drowsiness, euphoria, amnesia and dreamless sleep
- From plants can be deadly aka nightshade and henbane
