acetylcholine synthesis, storage, release, mechanism of action, diseases, related factors, receptors, function of receptors & neurotransmitters & its functions

1. Biosynthesis
Acetylcholine is biosynthesized
in cholinergic neurons by the
enzyme-catalyzed transfer of
the acetyl group from acetyl
coenzyme A (acetyl-S-CoA) to
choline, a quaternary
ammonium alcohol (Fig. 9.9)
The enzyme catalyzing this reaction, choline acetyltransferase, is also
biosynthesized in the cholinergic neuron. Choline used for biosynthesis of
acetylcholine in the CNS comes from several sources. About 35% to 50% of the
choline produced by AChE-catalyzed hydrolysis of acetylcholine in the synaptic
spaceis transported into the neuron (see below). This accounts for about half of the
choline required for acetylcholine synthesis (30).
#two stores of choline are
the lipid phosphatidylcholine, found in the plasma, and
phosphorylcholine, stored in lipid.
Although, choline will not cross the blood–brain barrier, phosphatidylcholine and
phosphorylcholine will.
Once in the CNS, these phosphatidylcholine esters can be hydrolyzed to afford
choline (30). Choline canbe biosynthesizedfromthe amino acidserine (Fig. 9.9),
but most of the choline used to form acetylcholine is recycled after AChE-
catalyzed hydrolysis of acetylcholine in the synaptic space. The choline

2. acetyltransferase- catalyzed reaction is not the rate-limiting step in acetylcholine
biosynthesis.
Active uptake of choline into the neuron is rate-determining . Choline is taken up
into cells by both low-affinity and high-affinity transport sites.
The low-affinity (Km = 10 to 100 μM) transporter is found in cells that
synthesize choline-containing phospholipids (e.g., corneal epithelium).
The high-affinity (Km = 1 to 5 μM) transporter is a sodium-choline
cotransporter and is found in cholinergic nerve endings, where it is
responsible for uptake of most of the choline recycled from the synapse(30).
Because this high-affinity uptake site is saturable at greater than 10 μM, the
rate of choline uptake by the neuron is limited. Thus, choline uptake is
considered to be the rate-determining step in biosynthesis of acetylcholine.
Hemicholinium-3 is a research tool that inhibits reuptake of choline at high-
affinity uptake sites.
Storage
Most newly biosynthesized
 acetylcholine is actively transported into cytosolic storagevesicles located in
presynaptic nerve endings,
 where it is maintained with adenosine triphosphate (ATP) (10:1 ratio)
 along with calcium and magnesium ions until it is released.
 Some acetylcholine remains in the cytosol and eventually is hydrolyzed.
 Only the stored form serves as the functional neurotransmitter.

3. Release
 Release of acetylcholine from the storage vesicles is initiated by an action
potential that has traveled down the axon to the presynaptic nerve membrane.
 This action potential leads to opening of voltage-dependent calcium
channels,
 affording an influx of Ca2+
 and exocytotic release of acetylcholine into the synapse.
 The increase in intracellular Ca2+ can induce fusion of acetylcholine storage
vesicles with the presynaptic membrane before release of the
neurotransmitter. Each synaptic vesicle contains a quantum of acetylcholine;
one quantum represents between 12,000 and 60,000 molecules of
acetylcholine. A single action potential causes release of several hundred
quanta of acetylcholine into the synapse.
an action potential
opening of voltage-dependent calcium channels,
influx of Ca2+
exocytotic release of acetylcholine into the synapse.
 Why Ach not used in therapeutically?
 Ach is a poor therapeutic agent due to its lack of specificity for nAChRs or
mAChRs and
 due to the chemical and physicochemical properties associated with its ester
and quaternary ammonium salt functional groups.
 It is quite stable in the solid crystalline form but undergoes rapid hydrolysis
in aqueous solution.

4.  This hydrolysis is accelerated in the presence of catalytic amounts of either
acid or base.
For this reason, acetylcholine cannot be administered orally due to rapid
hydrolysis in the gastrointestinal tract.
Even when administered parenterally,
 Its pharmacologic action is fleeting as a result of hydrolysis by
butyrylcholinesterase (also known as pseudocholinesterase or plasma
cholinesterase) in serum.
 The quaternary ammonium functional group of acetylcholine imparts
excellent water solubility, but quaternary ammonium salts are poorly
absorbed across lipid membranes due to their high hydrophilic and ionic
character.
 Thus, even if acetylcholine were stable enough to be administered orally, it
would be poorly absorbed.
When used during ocular surgery to produce complete miosis within seconds,
acetylcholine must be directly instilled into the anterior chamber. It cannot be
administered topically, because it is not lipophilic enough to penetrate the cornea,
and it must be reconstitution immediately before instillation due to its hydrolytic
lability.

5. Nts: Nts are chemical substances that are responsible for transmission an impulse
through a synapse. e.g. Ach, dopamine, Ep , Nep, serotonin etc.
Receptor: Receptor is a large protein
molecules which are interacts with drug
molecules to trigger a response.