Synthesis, storage & release
Precursors: choline and Acetyl CoA
Enzyme: choline acetyltransferase
Products: acetylcholine and Coenzyme A
Choline – two major sources
1. From diet – found in vegetables, egg yolk, kidneys, liver, seeds, and legumes. It enters
the brain through specific carrier systems in the membrane of the capillary endothelial
cells. This blood-brain barrier choline transporter is bidirectional.
You can’t eat a lot of food containing choline, because there is a limit to the transport!
2. From previously released Ach – via a Na dependent high-affinity uptake mechanism.
This mechanism is estimated to recycle 35 to 50% of all liberated choline back into Ach
Acetyl CoA = acetyl group + coenzyme A
Synthesized in mitochondria (which contains coenzyme A) and derived from the metabolism
of sugar and fats.
Transport to cytoplasm is Ca dependent.
Choline acetyltransferase (ChAT)
Synthesized in the rER and transported via axoplasmic transport to the axon terminal. Most
ChAT exist freely in the cytoplasm of nerve terminal. ChAT is considered to be a selective
marker for cholinergic neurons (you can stain this enzyme to look for cholinergic neurons)
There are 3 factors regulating ACh synthesis
This as negative feedback system, where ACh binds to an allosteric binding site on ChAT,
changing its 3D structure, and thus reducing its catalytic activity.
The rate of ACh formation depends on the concentration of the precursor. There will be also an
increased rate of production if there is a lot of release of acetylcholine (gap in the concentration,
so the reaction goes faster). Thus, the administration of choline can enhance ACh synthesis, but
only in Ach terminals that have been depleted because of ACh release. Neuronal activity
ACh release increases ACh synthesis:
1) More ACh enters the vesicles from the cytoplasm
2) Increase in free choline in the synapse
3) Ca entrance in the terminal increases the rate of transport of acetyl CoA from the
mitochondria to the cytoplasm.
It is responsible for acetylcholine breakdown into choline and acetic acid. There is no
acetylcholine transporter, so you have to break it down so that the choline can be up taken by
AChE is found in:
1- Pre-synaptic, in the cholinergic neuron
2- In the membrane of the post-synaptic cell
3- At neuromuscular junctions, released by muscle cells
Drugs that affect ACh synthesis, storage, release, and inactivation
Blockade of ACh synthesis
- Some drugs can inhibit ChAT activity, but they are not selective.
- Some drugs can inhibit the high-affinity choline transporter
o Hemicholinium-3 (HC-3) – but it does not cross the BBB
Blockade of ACh storage
If you block the storage you also influence the release and synthesis.
- Vesamicol inhibits the vesicular ACh transporter
Blockade of ACh release
- Botulinum Toxin (clostridium botulinum bacterium) – is very selective to cholinergic
neurons; paralysis and asphyxiation
- Tetanus Toxin (Clostridium tetani bacterium) – spastic paralysis, severe convulsions
and death. Not quite selective to ACh as BT.
Blockade of ACh inactivation
Anticholinesterase agents increase the duration of action of ACh at cholinergic receptor sites by
blocking ACh hydrolysis by AChE. In most cases, this is accomplished by competing with ACh
for access to the active binding site of the AChE molecule.
Reversible acetylcholinesterase inhibitors
- Physostigmine (found in the seeds of a Nigerian plant) – readily crosses the BBB
producing: slurred speech, confusion, loss of reflexes, convulsion, coma & death. - Neostigmine (a synthetic analog of Physostigmine, less lipid soluble) – does not cross
the BBB and it is used clinically for the management of Myasthenia gravis, an
autoimmune disorder whereby antibodies bind and eventually break down ACh receptors
Irreversible acetylcholinesterase inhibitors
Synthetic organophosphorous compounds that form highly stable phosphorylated complexes
with AChE that resist cleavage for hours or for ever! Your body tries to compensate making
more enzyme, because there is no way of breaking that binding.
- Parathion - used as an insecticide
- Malathion – much less toxic to mammals and birds
- Nerve gases – Sarin, Soman and tabum (II World War, Germany) – 1 mg or less, if
inhaled, readily cross the BBB and cause intense sweating, filling of bronchial passages
with mucus, bronchial constriction, dimmed vision, uncontrollable vomiting and
defecation, convulsions, paralysis and death.
Peripheral cholinergic systems
Preganglionic neuron = cholinergic neuron (releases ACh) – travels a long distance
Postganglionic neuron = cholinergic neuron (releases ACh) Sympathetic branch
Preganglionic neuron = cholinergic - their axons project for a relatively short distance before
they synapse with sympathetic ganglia
Postganglionic neuron = noradrenergic neuron (releases norepinephrine)
Widespread involvement of ACh in both the neuromuscular and autonomic systems explains
why drugs that interfere with this transmitter exert such powerful physiological effects and
sometimes are highly toxic.
Central cholinergic systems
1. Interneurons of the striatal complex
- Small and medium neurons are found in this area
- It works with the limbic system to control motivated behavior
- The dorsal portion is involved in motor behavior
2. Projection neurons of the basal forebrain (BFCS)
- All these regions have different locations and cholinergic groups
- This region overall is known to be depleted of cholinergic cells in people with Alzheimer’s
o Rostral (anterior) basal forebrain: Ch1 – medial septum; Ch2 – vertical diagonal
band of Broca
o Medial basal forebrain: Ch3 – horizontal limb diagonal band of Broca o Caudal (posterior) basal forebrain: Ch4 – nucleus basalis and substantia
3. Pontomesencephalic cell groups
- Projections of posterior and anterior areas
o Ch5 – peduncolopontine tegmental nucleus
o Ch6 – laterodorsal tegmental nucleus
1. Muscarinic receptors
a. Activated by muscarine, an alkaloid found in a mushroom
b. Their responses can be excitatory or inhibitory
c. Their activation has long latency of onset (at least 100 ms)
d. G protein-coupled receptors
2. Nicotinic receptors
a. Activated by nicotine
b. Their responses are always excitatory
c. Their activation has a short latency (few ms)
d. Ligand-gated channels (typically activated through a sodium channel)
- They can be homo or heteropentamers
- Neuronal receptors and muscle receptors during fetal developme