Acetylcholine

Dr. Muzaffar Abbas

Acetylcholine
Acetylcholine is a neurochemical that has a wide
variety of functions in the brain and other organ
systems of the body. Specifically, it is a
neurotransmitter that acts as a chemical message that
is released by neurons and allows them to
communicate with one another and other specialized
cells such as myocytes and cells found in glandular
tissues.
Cholinergic transmission
 Choline is transported into the presynaptic nerve
terminal by a sodium-dependent choline transporter
(CHT). This transporter can be inhibited by
hemicholinium drugs.
In the cytoplasm, acetylcholine is synthesized from
choline and acetyl-CoA (AcCoA) by the enzyme
choline acetyltransferase (ChAT).
Acetylcholine (ACh) is then transported into the
storage vesicle by a vesicle-associated transporter
(VAT), which can be inhibited by vesamicol.
Peptides (P), adenosine triphosphate (ATP), and
proteoglycan are also stored in the vesicle.
Release of transmitters occurs when 3
voltage-sensitive calcium channels in the terminal
membrane are opened, allowing an influx of calcium.
The resulting increase in intracellular calcium
causes fusion of vesicles with the surface membrane
and exocytotic expulsion of acetylcholine and
cotransmitters into the junctional cleft. This step can
be blocked by botulinum toxin.
Acetylcholine’s action is terminated by metabolism
by the enzyme acetylcholinesterase. Receptors on the
presynaptic nerve ending modulate transmitter
release.

4
Events and sites of drug action at a nicotinic cholinergic synapse. Acetylcholine (ACh) is shown acting postsynaptically
on a nicotinic receptor controlling a cation channel (e.g. at the neuromuscular or ganglionic synapse), and also on a
presynaptic nicotinic receptor that acts to facilitate ACh release during sustained synaptic activity. The nerve terminal also
contains acetylcholinesterase (not shown); when this is inhibited, the amount of free ACh, and the rate of leakage of ACh
via the choline carrier, is increased. Under normal conditions, this leakage of ACh is insignificant. At muscarinic
cholinergic junctions (e.g. heart, smooth muscle and exocrine glands), both postsynaptic and presynaptic (inhibitory)
receptors are of the muscarinic type. AcCoA, acetyl coenzyme A; AChE, acetylcholinesterase; CAT, 5choline
acetyltransferase; CoA, coenzyme A.
Source: Basic &
Clinical
Pharmacology, 14th
ed Page 94

Schematic illustration of a generalized cholinergic junction 6

Source: Goodman
and Gilman’s
Pharmacology, 14th
ed Page 47

A cholinergic neuroeffector junction. 7

 Source: Ganong
Physiology, 23rd
Ed, page 264

Figure: Organization of sympathetic (left) and parasympathetic (right) nervous systems. Preganglionic sympathetic and
parasympathetic neurons are shown in red and orange, respectively; postganglionic sympathetic and parasympathetic
neurons in blue and green, respectively 8
1.Muscarinic receptors (G-protein coupled, Gs, Gi
and Gq)
Muscarinic receptors (M1-M5) contain seven
transmembrane domains whose third cytoplasmic
loop is coupled to G proteins that function as
transducer and are located on
Plasma membranes of cells in the central nervous
system
Organs innervated by post ganglionic
parasympathetic nerves
Some tissues that are not innervated by post
ganglionic parasympathetic nerves e.g, endothelial
cells.
Tissues innervated by postganglionic 9
sympathetic cholinergic nerve.
The odd-numbered members of the group (M1, M3,
M5) couple with Gq to activate the inositol phosphate
pathway while the even-numbered receptors (M2,
M4) open potassium (KATP) channels causing
membrane hyperpolarization as well as acting
through Gi to inhibit adenylyl cyclase and thus
reduce intracellular cAMP.

10
Neuronal nicotinic acetylcholine receptors
Neuronal nicotinic acetylcholine receptors (nAChRs)
are a family of cation channels widely distributed in
the brain. Nicotinic acetylcholine receptors
(nAChRs) warrant attention, as they play many
critical roles in brain and body function and have
been implicated in a number of neurological and
psychiatric disorders.

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The nAChR Subtypes Localization in the
Brain

Gotti el al., (2006) Trends in Pharmacological Sciences. 27:482-491.

Fig. 1; Nicotinic acetylcholine receptors (nAChRs) are pentameric proteins composed of homologous nAChR
subunits; they are part of the large superfamily of dicysteine loop (Cys-loop) ligand-gated ion channels,
which also includes GABA-gated chloride channels, glycine-gated chloride channels, and serotonin (5-HT)-
gated cation channels. The tree shows that mammals possess 16 nAChR genes, whereas an additional subunit
type (α8) has been found in chicken and pufferfish. nAChRs are expressed in muscle and in the nervous
system, with the most abundant brain types consisting of α7, α4β2, and α3β4. The α7 subunits form
homomeric nAChRs, whereas α4β2 and α3β4 form heteromeric receptors. α4β2 heteromers can exist 13
as two
distinct stoichiometric arrangements
Brain Cholinergic Pathways
Acetylcholine is released from neurons projecting to
a broad range of cortical and sub cortical sites. These
projections can be split into two groups: the
magnocellular basal forebrain cholinergic system and
the brain stem cholinergic system.
 The basal forebrain cholinergic system includes
cells located in the medial septal nucleus (MS), the
vertical, and horizontal limbs of the diagonal band
of Broca (DB), and the nucleus basalis
magnocellularis (nBM; i.e., nucleus basalis of
Meynert). These structures send cholinergic (as well
as noncholinergic) projections to a broad range of
sites in the neocortex as well as limbic
cortices such as cingulate cortex, entorhinal cortex
and hippocampus.
The brainstem cholinergic system, which includes
neurons located in the pedunculopontine tegmental
nucleus (PPT) and laterodorsal pontine
tegmentum (LDT) principally innervate the
thalamus and basal ganglia but also innervates the
basal forebrain and serves as a minor component of
the cholinergic innervation of cortical structures.
 .

Major cholinergic projections of the central nervous system. Two groups of projections exist: the magnocellular basal
forebrain cholinergic system and the brainstem cholinergic system. The magnocellular basal forebrain cholinergic system
includes the medial septal nucleus (MS), the vertical and horizontal limbs of the diagonal band of Broca (DB), and the
nucleus basalis magnocellularis (nBM). The horizontal limb of the DB and nBM has extensive diffuse projections to
neocortex as well as projections to basolateral amygdala and olfactory bulb (these latter two are not shown here). The MS
and vertical limb of the DB project to hippocampus and entorhinal cortices. The brainstem cholinergic system includes the
pedunculopontine tegmental nucleus (PPT) and laterodorsal pontine tegmentum (LDT) and projects predominantly to the
thalamus but also to the basal forebrain region
FIGURE 1. OVERVIEW OF THE BASAL FOREBRAIN (BF) CHOLINERGIC PATHWAY.
The BF cholinergic system of the Sprague-Dawley rats includes the medial septum (MS),
vertical limbs of the diagonal band of Broca (vDB), nucleus basalis of Meynert (NBM), and
substantia innominate (SI). The vDB and NBM have diffuse projections to all parts of the
neocortex and to basolateral amygdala and olfactory bulb (these latter two are not shown here).
The MS and vDB project to hippocampus. Besides, the brainstem cholinergic system
projects to the thalamus and hypothalamus but also to the BF region. This system includes
the pedunculopontine tegmental nucleus (PPT) and laterodorsal pontine tegmentum (LDT). 17
Acetylcholine in the Central Nervous System
Within the brain, acetylcholine has involvement in
memory, motivation, arousal, and attention.
Acetylcholine originates from two major places in
the brain: 1) basal forebrain and 2) the
mesopontine tegmentum area.
Acetylcholine originates in the basal forebrain
from both the basal nucleus of Meynert and the
medial septal nucleus.
The basal nucleus of Meynert works on the M1
receptors within the neocortex.
The medial septal nucleus functions in the
hippocampus and parts of the cerebral cortex at the
M1 receptors.
 The mesopontine tegmentum is in the brain stem,
and acetylcholine comes from its
pedunculopontine nucleus and laterodorsal
tegmental nucleus.
 The mesopontine tegmentum mainly activates
the M1 receptors in the brainstem. The M1
receptors in the brainstem are present in the raphe
nucleus, lateral reticular nucleus, deep cerebellar
nuclei, pontine nuclei, locus coeruleus, and the
inferior olive. However, the mesopontine
tegmentum also projects to the basal ganglia,
thalamus, basal forebrain, and tectum.
 Acetylcholine is known to have effects on a
person's memory. For example, drugs such as
scopolamine, an anticholinergic that works
primarily at M1 receptors, prevent the learning of
new information.
Also, studies have shown that acetylcholine is
essential in the neocortex to learn simple tasks of
discrimination.
In the hippocampus, the absence of acetylcholine
causes forgetfulness.
Alzheimer’s disease
Alzheimer’s disease refers to dementia that does
not have an antecedent cause, such as stroke, brain
trauma or alcohol.
The term dementia is used to describe progressive
loss of cognitive function rather than being
‘demented’, i.e. behaving irrationally due to anger.

(amyloid precursor protein, APP)

Pathogenesis of Alzheimer’s disease
Alzheimer’s disease is associated with brain
shrinkage and localized loss of cholinergic neurons,
mainly in the hippocampus and frontal cortex.
Two microscopic features are characteristic of the
disease, namely extracellular amyloid plaques,
consisting of amorphous extracellular deposits of β-
amyloid protein (known as Aβ), and intraneuronal
neurofibrillary tangles, comprising filaments of a
phosphorylated form of a microtubule-associated
protein (Tau). Both of these deposits are protein
aggregates that result from misfolding of native
proteins.
 Amyloid deposits consist of aggregates of Aβ, a
40- or 42-residue segment of APP, generated by
the action of specific proteases (secretases).
 Aβ40 is produced normally in small amounts,
whereas Aβ42 is overproduced as a result of the
genetic mutations mentioned above. Both proteins
aggregate to form amyloid plaques, but Aβ42
shows a stronger tendency than Aβ40 to do so,
and appears to be the main culprit in amyloid
formation.
 It is uncertain exactly how Aβ accumulation
causes neurodegeneration, and whether the
damage is done by soluble Aβ monomers or
oligomers or by amyloid plaques. There is
evidence that the cells die by apoptosis, although
an inflammatory response is also evident.
Expression of Alzheimer mutations in transgenic
animals causes plaque formation and
neurodegeneration, and also increases the
susceptibility of CNS neurons to other challenges,
such as ischaemia, excitotoxicity and oxidative stress,
and this increased vulnerability may be the cause of
the progressive neurodegeneration in AD.
Tau is abnormally phosphorylated by the action of
various kinases, including glycogen synthase
kinase-3β (GSK-3β) and cyclin-dependent kinase 5
(CDK5), and dissociates from microtubules to be
deposited intracellularly. When the cells die, these
filaments aggregate as
extracellular neurofibrillary tangles.
26
Pathogenesis of Alzheimer’s disease. [A] Structure of amyloid precursor
protein (APP), showing origin of secreted APP (sAPP) and Aβ amyloid
protein. The regions involved in amyloidogenic mutations discovered in
some cases of familial Alzheimer’s disease are shown flanking the Aβ
sequence. APP cleavage involves three proteases: secretases α, β and γ. α-
Secretase produces soluble APP, whereas β- and γ-secretases generate Aβ
amyloid protein. γ-Secretase can cut at different points, generating Aβ
peptides of varying lengths, including Aβ40 and Aβ42, the latter having a
high tendency to aggregate as amyloid plaques. [B] Processing of APP.
The main ‘physiological’ pathway gives rise to sAPP, which exerts a
number of trophic functions. Cleavage of APP at different sites gives rise
to Aβ, the predominant form normally being Aβ40, which is weakly
amyloidogenic. Mutations in APP or presenilins increase the proportion of
APP, which is degraded via the amyloidogenic pathway, and also increase
the proportion converted to the much more strongly amyloidogenic form
Aβ42. Clearance of Aβ is impaired by mutations in the apoE4 gene.
Hyperphosphorylated Tau results in dissociation of Tau from
microtubules, misfolding and aggregation to form paired helical filaments,
which enhance Aβ toxicity. 27
Loss of cholinergic neurons
A deficiency of intact cholinergic neurons,
particularly those extending from subcortical areas
such as the nucleus basalis, has been observed in
patients with progressive dementia of the Alzheimer
type.
Choline acetyl transferase activity, acetylcholine
content and acetylcholinesterase and choline
transport in the cortex and hippocampus are all
reduced considerably in AD but not in other
disorders, such as depression or schizophrenia.
Muscarinic receptor density, determined by binding
studies, is not affected, but nicotinic receptors,
particularly in the cortex, are reduced.
 The reason for the selective loss of cholinergic
neurons resulting from Aβ formation is not known.
Therapeutic approaches
1. Cholinesterase inhibitors
Tacrine
Donepezil,
Rivastigmine
Galantamine
Mechanism

Action of anticholinesterase drugs. Reversible anticholinesterase (neostigmine): recovery of

activity by hydrolysis of the carbamylated enzyme takes many minutes. Irreversible
anticholinesterase (dyflos): reactivation of phosphorylated enzyme by pralidoxime. 31