Topic 4: Acetylcholine Flashcards
What are the six criteria for neurotransmitters?
presynaptic cell should contain the substance as well as a mechanism to synthesize it
substance should be released when depolarizing stimulus is applied to the neuron
receptors should be present on the postsynaptic cell
known antagonists should block the effects
a system to inactivate the substance must exist
exogenous application of the substance to the postsynaptic cell should produce the same response
What are neuromodulators?
can be hormone-like (acting at a distance)
may act at locations other than the synapse
does not elicit a direct effect on the postsynaptic cell, but alters the action of a classical neurotransmitter (enhances, reduces, or prolongs NT action)
may function in anterograde or retrograde manner
may be released from glial cells
What are types of neuromodulators?
autocrine (self-acting)
juxtacrine (adjacent)
paracrine (near)
endocrine (far)
exocrine (outside)
What is acetylcholine?
acetylcholine was the first neurotransmitter identified, used in seminal experiments to determine the nature of chemical transmission at the synapse
common neurotransmitter at neuromuscular junctions in the periphery
neurons that use acetylcholine are termed cholinergic neurons
What is the process of the synthesis of acetylcholine?
acetyl-coenzyme A + choline —(ChAT)—> acetylcholine
synthesis of acetylcholine by choline acetyltransferase (ChAT)
How can ChAT expression identify cholinergic neurons?
immunofluorescence micrograph of cholinergic motor neurons in the ventral horn of the spinal cord
ChAT is only expressed in the cytoplasm of neurons that use ACh as a neurotransmitter
What is choline?
choline is derived primarily from hydrolysis of dietary lipids (phosphatidylcholines) by phospholipase D
choline is water soluble and is only capable of crossing the BBB due to the presence of specific choline transporters
rich in protein foods
increased levels in endurance athletes and alcoholics
How is acetylcholine metabolized?
acetylcholine —(AChE)—> choline + acetate
acetylcholine is metabolized to choline and acetic acid/acetate by the enzyme acetylcholinesterase (AChE)
How is ACh synthesis tightly regulated?
product inhibition: high levels of ACh in the cell inhibit the synthesis of further ACh by ChAT
precursor availability (choline and acetyl-CoA): increasing dietary choline has been explored as a treatment for conditions where the cholinergic system has been damaged (e.g., Alzheimer’s) - but not to any significant success
neuron activity (increased during high activity): activity-dependent synthesis ensures sufficient ACh is available during periods of high activity
How is ACh stored?
stored in vesicles at the nerve terminal by vesicular ACh transporter
transport is inhibited by the drug vesamicol: leads to cytosolic accumulation of ACh, decreased release
blocking vesicle transport depletes the pool of release-ready vesicles
How is ACh released?
released by classical vesicular exocytosis (voltage-dependent Ca2+-influx)
release triggered by latrotoxin (black widow venom) in periphery
muscle pai, tremors, nausea, excessive sweating
What is acetylcholine re-uptake?
ACh is broke down in the synapse to attenuate signaling: AChE is present primarily in the synaptic cleft and breaks ACh down to choline
breakdown product (choline) transported by choline transporter
majority of choline is recycled to ACh
re-uptake inhibited by the drug hemicholinium-3: leads to synaptic accumulation of choline and run-down activity
What is botox?
clostridial neurotoxins (isolated from Clostridium botulinum) cause paralytic effects of botulism poisoning
BoNT A/B are proteases that cleave VAMP or SNAP-25 (resp.) to prevent vesicle binding
local injection causes muscle paralysis by inhibiting ACh release
therapeutic use includes treatment of crossed eyes, eyelid spasms, facial spasms
How do insecticides interact with acetylcholine?
many drugs affecting cholinergic systems are insecticidal
ACh is a primary neurotransmitter of the insect CNS
plant alkyloids are secondary metabolites commonly synthesized for defense against insect or animal predation
several plant alkyloids affecting ACh are exploited for commercial or therapeutic benefit
What drugs affect ACh breakdown?
AChE inhibition prolongs ACh signalling
AChE inhibition decreases the rate of ACh breakdown in the synaptic cleft leaving more ACh to act at postsynaptic receptors
plant-derived toxin physostigmine is BB permeable inhibitor of AChE (found in Calabar beans): accidental poisoning leads to slurred speech, confusion, hallucinations, loss of reflexes, convulsions, coma, death
synthetic BBB-impermeable analogues neostigmine (Prostigmin) and pyridostigmine (Mestionon) are used to treat the autoimmune disease myasthenia gravis (MG)
physostigmine, pyridostigmine, and neostigmine are reversible inhibitors of AChE
