Acetylcholine
Paul M Salvaterra, Beckman Research Institute, Duarte, California, USA
Acetylcholine is a neurotransmitter found in the nervous systems of all animals. It is involved
in the control of functions as diverse as locomotion, digestion, cardiac rate, ‘fight and flight’
responses, secretion, learning and memory. Cholinergic dysfunction is associated with
neuromuscular diseases such as myasthenia gravis and neurodegenerative disorders such
as Alzheimer disease.
Introduction
Studies of acetylcholine and cholinergic neurotransmis-
sion have played a key role in the development of nearly all
aspects of our current understanding of chemical synaptic
transmission. In the early part of the twentieth century,
pioneering physiological and neurochemical experiments
resulted in establishing the principle that release of
neuroactive compounds, such as acetylcholine, on to
effector cells or other neurons forms the basis of most
types of intercellular communication. In these early
studies, application of acetylcholine could mimic the
effects of nerve stimulation on muscle contraction, the
rate of heart beating, etc., and the compound was thus
identified as the first neurotransmitter substance. It was
also noted that not all nerves released acetylcholine when
stimulated, thus indicating specificity for the type of
neurotransmitter substances present in particular neurons.
Pharmacological work identified compounds, extracted
primarily from plants, which differentially blocked the
action of acetylcholine on particular types of effector cells,
leading to the concept of receptor specificity. The quantal
nature of neurotransmitter release was also first appre-
ciated at cholinergic neuromuscular junctions. Finally, the
nicotinic acetylcholine receptor was the first ligand-gated
ion channel to have its amino acid sequence established.
Acetylcholine is a simple ester of the quaternary amino
alcohol choline and acetic acid. Acetylcholine is positively
charged at physiological pH, is freely soluble in water
(usually supplied as a bromide or chloride salt) and is
subject to rapid hydrolysis in solution by heat or alkali.
Nuclear magnetic resonance studies indicate considerable
flexibility of the molecule in solution, and different
conformations are thought to bind to different types of
acetylcholine receptor.
Acetylcholine functions primarily as a chemical neuro-
transmitter in the nervous systems of all animals. When a
cholinergic neuron is excited, it releases transmitter into the
synaptic cleft where it can bind to a number of different
receptor proteins. The receptors for acetylcholine can be
classified into two general categories based primarily on
the actions of different plant alkaloids that affect their
function: nicotinic (nicotine binding) or muscarinic (mus-
carine binding). Several different subtypes for each of these
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Introductory article
Article Contents
. Introduction
. Major Neurotransmitter in Vertebrate Nervous
System: Neuromuscular Junction, Ganglia, Brain
. Major Neurotransmitter in Many Invertebrate
Nervous Systems
. Biosynthesis of Acetylcholine
. Properties and Localization of Choline
Acetyltransferase
. Degradation of Acetylcholine
. Properties and Localization of Acetylcholinesterase
. Packaging Acetylcholine into Synaptic Vesicles
. Properties and Localization of the Vesicular
Acetylcholine Transporter
. Diseases Associated with Cholinergic Dysfunction
. Acetylcholinesterase Inhibitors: Use as Insecticides,
in Chemical Warfare and as Therapeutic Agents
. Summary
general receptor classes have been characterized. The
receptor binding event can be transduced into opening of
cationic or anionic ion channels or coupled to some other
metabolic signal such as phospholipid turnover rates or
activation of second-messenger systems. Both inhibitory
or, more commonly, excitatory responses are induced in
the neurons or effector cells which receive the neurotrans-
mitter signal, making acetylcholine-mediated neurotrans-
mission particularly versatile.
In addition to the ubiquitous presence of acetylcholine in
the nervous systems of all animals, it is also found in a
limited number of plants, bacteria, fungi and protozoa.
This widespread distribution in a variety of species most
likely indicates the appearance of acetylcholine-metaboliz-
ing proteins fairly early in evolutionary history. In
vertebrates, acetylcholine is also found in non-neuronal
tissues such as primate placenta and sperm where its
functional role, if any, remains unknown.
Major Neurotransmitter in Vertebrate
Nervous System: Neuromuscular
Junction, Ganglia, Brain
Acetylcholine is found in, and used by, a wide variety of
vertebrate neurons to carry out diverse functional roles. All
vertebrate motor nuclei and spinal cord motor neurons
make and use acetylcholine as a neurotransmitter for
signalling skeletal muscles to contract. Motor activities
such as locomotion, eye blinking, facial expressions, etc.
are thus critically dependent on functioning cholinergic
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 Acetylcholine

synaptic neurotransmission. Involuntary smooth muscle cholinergic neurotransmission in other species. Molluscs
action also depends on acetylcholine neurotransmission. such as the sea slug Aplysia have a variety of identified
Activity such as diaphragm contraction (i.e. breathing) cholinergic neurons in their CNS which have been studied
and gut contraction as well as excretory functions rely at extensively. At least three types of ionic channel-mediated
least in part on cholinergic neurotransmission. Heart responses have been characterized following activation of
muscle responds to acetylcholine by slowing the rate of different types of acetylcholine receptors. In nematodes
heart beating. Acetylcholine is also used as a transmitter in and annelids, acetylcholine can function as an excitatory
the preganglionic neurons of the sympathetic branch of the neuromuscular transmitter in contrast to most other
autonomic nervous system and for parasympathetic invertebrates which apparently use glutamate for this
postganglionic neurons. Cholinergic neurotransmission purpose.
thus plays an important role in regulating responses to
stress or adverse environmental conditions, as well as
maintaining internal homeostasis, in most animals. Tem-
perature regulation through sweating and salivary secre-
Biosynthesis of Acetylcholine
tion is regulated by acetylcholine. In the brain,
Acetylcholine biosynthesis is accomplished by esterifica-
acetylcholine-containing neurons are found to be broadly
tion of an activated acetyl group from coenzyme A with the
distributed with especially high concentrations in the basal
tertiary amino alcohol choline. The reaction, shown in
forebrain nuclei (basal nucleus, the diagonal band of Broca
Figure 1, is catalysed by the enzyme acetyl-coenzyme A-
and the medial septum), the caudate nucleus and promi-
choline-O-acetyltransferase (choline acetyltransferase)
nent cholinergic inputs to the hippocampus. Cortical
and in nervous system is thought to take place specifically
cholinergic neurons have been observed in certain species.
in cholinergic neurons. The acetyl-coenzyme A used for
While the specific functions of most central nervous system
acetylcholine biosynthesis is derived from mitochondrial
(CNS) cholinergic neurons are not known precisely, many
metabolism, whereas choline is derived from a variety of
pharmacological studies argue for a role in certain aspects
sources such as phospholipid turnover or reuptake of
of learning and memory or other higher-ordered thought
choline from the extracellular fluid following breakdown
processes. In addition to these primarily synaptic functions
of acetylcholine by hydrolysis. A specific Na 1 -dependent
of acetylcholine, the transmitter may also play a role in
high-affinity choline transporter is present on the plasma
blood pressure regulation by binding to nonsynaptic
membranes of cholinergic neurons. Several studies have
receptors in blood vessels or may control some aspects of
indicated that choline availability may be a rate-limiting
early development by interacting with cholinergic recep-
step for acetylcholine production. It may even be possible
tors on fertilized eggs.
to influence the levels of acetylcholine by ingesting high
The electric organs of Electrophorus and Torpedo are
levels of choline. One interesting facet of acetylcholine
embryologically related to skeletal muscle tissue and are
production is that the newly synthesized pool of neuro-
innervated primarily by a specialized CNS structure called
transmitter appears to be used preferentially for synaptic
the electric organ. The innervation is essentially purely
transmission, indicating possible coupling between trans-
cholinergic and, as a result, the brains of electric
mitter biosynthesis and release.
fish contain especially high levels of cholinergic macro-
molecules and acetylcholine relative to other types of
vertebrates.
Properties and Localization of Choline
Acetyltransferase
Major Neurotransmitter in Many
Choline acetyltransferase has been purified and character-
Invertebrate Nervous Systems ized from a variety of species including Drosophila,
nematodes, electric fish, rodents and humans. The enzyme
Acetylcholine is also used as a major neurotransmitter in a is a single-subunit soluble globular protein with an Mr of
variety of invertebrate neurons with diverse functional approximately 68 000. Multiple isoelectric forms of choline
roles. In most arthropods such as insects it is thought to be acetyltransferase have been observed but their significance
a primary sensory neurotransmitter for many types of is unknown and some may be generated artefactually
peripheral neurons innervating a variety of chemosensory
or mechanosensory specializations. Insects also contain
relatively high concentrations of acetylcholine in their Choline
CNS, they have high levels of cholinergic macromolecules, acetyltransferase
Acetyl-CoA + choline Acetylcholine + CoA-SH
and are particularly sensitive to application of antic-
holinergic compounds, which include a variety of organo- Figure 1 Biosynthesis of acetylcholine is catalysed by choline
phosphate insecticides and alkaloids known to effect acetyltransferase. CoA, coenzyme A.

2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net


during purification by proteolysis or other posttransla-
tional modifications. The vast majority of choline acetyl-
transferase protein (4 95%) is found in an aqueous
soluble form. A small proportion, however, appears to
require detergent treatment for solubilization. It is not
clear how the enzyme activity is associated with the
particulate cellular fractions or what its functional
significance is, although it has been suggested to participate
directly in ensuring that the transmitter is packaged into
synaptic vesicles.
Complementary deoxyribonucleic acid (cDNA) for
choline acetyltransferase has been cloned from a variety
of vertebrate and invertebrate species including Drosophi-
la, Caenorhabditis elegans, porcine, rodent and human. In
all species examined so far, there appears to be only a single
gene for choline acetyltransferase termed Cha. In humans
the genetic locus has been mapped to 10q11.2 by a variety
of approaches. In rodents and humans choline acetyl-
transferase messenger ribonucleic acids (mRNAs) appear
to be polymorphic as a result of a combination of
alternative mRNA splicing and/or the use of alternative
promoters to initiate transcription. In mice, for example,
three different alternative 5’ exons termed R, N and M
appear to be alternatively spliced to a common second
exon which contains the predicted codon for initiation of
protein translation. At least two different forms of choline
acetyltransferase mRNA have also been described in
humans. The functional significance of these alternative
forms of mRNA is not known and only a single form of
choline acetyltransferase mRNA has been observed in
invertebrates.
No vertebrate mutations in choline acetyltransferase
have been described. Genetic mutations have been isolated
and characterized in Drosophila and C. elegans. A number
of lethal alleles are also available for the invertebrate Cha
gene. Cha is an essential gene in Drosophila which shows
late embryonic lethality in animals null for Cha function.
Several temperature-sensitive conditional alleles have also
been described for Drosophila Cha, which result in a
number of interesting phenotypes such as paralysis,
reduced motor activity and abnormal courtship behaviour.
The nematode phenotype for hypomorphic Cha alleles is
motor uncoordination.
The localization of choline acetyltransferase has been
accomplished by enzymatic assay of microdissected
nervous system tissue as well as extensive immunocyto-
chemical and in situ hybridization studies. Choline
acetyltransferase is considered to be a reliable and specific
marker for cholinergic neurons and the presence of the
enzyme in a particular neuron is often taken as convincing
evidence that that particular cell makes and uses acetylcho-
line as a neurotransmitter. Biochemical assays of choline
acetyltransferase activity indicate that the highest levels are
found in insect nervous system, the electromotor nucleus of
electric fish and spinal cord ventral horn motor neurons.
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Acetylcholine
In vertebrate nervous system immunocytochemical
localization of choline acetyltransferase protein using a
variety of monoclonal and polyclonal antibodies has
revealed that the enzyme is present in all parts of
cholinergic neurons. Positive reaction product has been
observed in both symmetrical and asymmetrical synaptic
buttons, with the major type being symmetrical. Certain
groups of large projection neurons as well as local circuit
neurons appear to be cholinergic. In spinal cord large a
motor neurons as well as smaller g motor neurons,
preganglionic projections of the autonomic nervous
system, all stain with anticholine acetyltransferase anti-
body. In the brain choline acetyltransferase-positive
neurons and synaptic buttons are widely distributed and
include both local circuit as well as projection neurons. The
cholinergic projection neurons of the midbrain and
forebrain have been divided into eight groups (Ch1–Ch8)
based on their locations and projection patterns. They are
often interspersed with choline acetyltransferase-negative
neurons. Prominent cholinergic neurons have been found
in the medial septum, the vertical and horizontal limbs of
the diagonal band, the nucleus basalis, the postmesence-
phalic reticular formation, the medial habenula, the
parabigeminal nucleus and the motor neurons of cranial
nerve nuclei. Terminal fields containing choline acetyl-
transferase-positive synaptic buttons have been described
in the thalamus, interpeduncular nucleus, superior colli-
culus, hippocampus and cerebral cortex. Regions of the
CNS containing choline acetyltransferase-positive intrin-
sic neurons include the spinal cord, cerebral cortex,
amygdaloid complex, neostriatum, ventral striatum, ol-
factory bulb, retina and hypothalamus.
In invertebrates, such as Drosophila, choline acetyl-
transferase-positive neurons have been localized in many
regions of the central and peripheral nervous system, and
in general the localization is consistent with functions
related to acquisition or processing of primary sensory
information. Surprisingly, mutant Drosophila which have
a wild-type cDNA transgene as their only source of choline
acetyltransferase appear to have fairly normal behavioural
functions, even when the pattern of transgene expression is
quite different from the normal choline acetyltransferase
expression pattern.
Degradation of Acetylcholine
Acetylcholine action is terminated by hydrolysis of the
transmitter into free choline and acetate. The reaction at
synapses is catalysed by the enzyme acetylcholinesterase,
as shown in Figure 2. Other esterases that hydrolyse
acetylcholine, such as butyryl or pseudocholinesterases,
are also present at nonsynaptic sites, but their contribution
to transmitter inactivation in vivo is unknown. Inactivation
of transmitter by hydrolysis is rather unusual for small-
3
 Acetylcholine
Acetylcholinesterase
Acetylcholine Choline + acetate
Figure 2 Hydrolysis of acetylcholine is catalysed by acetylcholinesterase.
molecule neurotransmitters since the actions of most
others are terminated by removal of transmitter from the
synaptic cleft by specific high-affinity uptake systems
located in the plasma membrane of releasing neurons
and/or nearby cells. Most cholinergic neurons do, how-
ever, contain a specific plasma membrane Na 1 -dependent
high-affinity choline uptake system, which is believed to
recover approximately 50% of the choline used for
acetylcholine synthesis.
Properties and Localization of
Acetylcholinesterase
Acetylcholinesterase exists in a number of molecular forms
which appear to convert the enzyme between soluble and
insoluble forms, but have no major effect on substrate
specificity or catalytic activity. One class of molecular
forms is made up of either monomers or homologous
combinations of dimeric or tetrameric subunits. Varying
degrees of posttranslational modification affect the hydro-
phobicity by adding a glycophospholipid to the C-terminal
carboxyl group of the protein(s). The lipid allows the
enzyme to be tethered to plasma membranes. The second
major class of acetylcholinesterases is made up of
combinations of heterologous subunits. These are com-
posed of up to 12 catalytic subunits linked by disulfide
bonds to collagen tail-containing subunits, giving the final
protein assembly a pronounced axial asymmetry. The
collagenous tail of asymmetrical acetylcholinesterase is
thought to localize this form of the enzyme to the basil
lamina in synaptic clefts of the neuromuscular junction.
Another type of acetylcholinesterase found in brain has a
phospholipid tail-containing subunit which facilitates
association with membranes.
Acetylcholinesterase has no obvious membrane-span-
ning domains and the protein is usually synthesized as a
secreted protein with a hydrophobic leader sequence. The
various forms of the enzyme have been purified from a
variety of vertebrate and invertebrate species, and cDNAs
have been isolated and characterized from several of these
species. The different molecular forms arise via alternative
splicing of a single gene transcript. Exons 1 and 2 are
identical for symmetrical and asymmetrical forms of the
protein. Alternative splicing to two different third exons
gives rise to distinct C-terminal proteins. The specific
attachment points for posttranslational modifications and
heterologous subunit assembly are contained within the
divergent third exon sequences. The three-dimensional
structure of acetylcholinesterase isolated from Torpedo
4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
californica has been determined. The catalytic mechanism
of acetylcholinesterase is analogous to that of the serine
proteases, even though there is no obvious primary
structural homology between the cholinesterases and
proteases.
Several lines of evidence have mapped the human
acetylcholinesterase gene to 7q22, while the pseudocholi-
nesterase gene is at 3q25.2. Other genetic studies have
established that acetylcholinesterase carries the YT blood
group antigenic determinant. Genetic studies in avians
have established that the multiple forms of acetylcholines-
terase are coded for by a single genetic locus. In Drosophila
several lethal and conditional alleles of the single
acetylcholinesterase locus have been described. Complete
absence of the enzyme results in late embryo lethality.
Temperature-sensitive mutants exhibit a number of
phenotypes which are similar to temperature-sensitive
choline acetyltransferase alleles. Nematodes have two
different acetylcholinesterase genes, ace-1 and ace-2.
The distribution of acetylcholinesterase is significantly
broader than that of choline acetyltransferase, making it
difficult to use immunocytochemical localization of this
protein as a specific marker for cholinergic neurons. The
enzyme is found in nearly all regions of the nervous system
that exhibit choline acetyltransferase activity and in many
places that do not. One interesting aspect of acetylcholi-
nesterase concerns its localization at neuromuscular
junctions. The greatest concentration of protein appears
to be situated at the tips of junctional folds. Transmitter
would thus be exposed to degradative enzyme activity,
which could inactivate it before binding to cholinergic
receptors located within the junctional folds. Apparently,
the acetylcholinesterase is rapidly saturated with substrate
during release of substantial quantities of transmitter from
activated neuromuscular junctions.
Packaging Acetylcholine into Synaptic
Vesicles
Acetylcholine is released at cholinergic synaptic sites in
response to invasion of a depolarizing current into the
presynaptic nerve terminal. The release process is Ca2 1
dependent and appears to involve synaptic vesicle fusion
with the presynaptic plasma membrane. Spontaneous
release of transmitter also occurs and has been statistically
characterized as quantal in nature. The physical picture of
a quantal unit of acetylcholine is thought to be the contents
of a single synaptic vesicle. Since synaptic vesicles are
ordinarily impermeable to acetylcholine, they depend on
the action of a specific vesicular transport protein to move
acetylcholine from its site of synthesis in the cytoplasm into
the internal lumen of synaptic vesicles. The protein
that accomplishes this process is called the vesicular
acetylcholine transporter. The transporter functions as

an acetylcholine–H 1 antiporter by exchanging protons
within the vesicle with cytoplasmic acetylcholine. The ratio
of the acetylcholine concentration inside a vesicle relative
to
the cytosol has been estimated to be about 100 : 1. The high
concentration of H 1 within vesicles, which serves as the
driving force for the transporter, is established by an ion-
motive adenosine triphosphatase.
Properties and Localization of the
Vesicular Acetylcholine Transporter
The vesicular acetylcholine transporter belongs to a fairly
large gene family composed of a number of transporters
which contain a general structure of 12 transmembrane-
spanning domains. Other members of this family include
the vesicular monoamine neurotransmitter transporters
and a variety of plasma membrane neurotransmitter
transporters. More distant relatives include sugar trans-
porters and some bacterial drug resistance genes. The size
of the vesicular acetylcholine transporter is approximately
60 kDa. The protein contains hydrophilic amino acid
residues at the N and C termini and a large potentially
glycosylated luminal loop between the first and second
transmembrane domains. The activity of the vesicular
acetylcholine transporter can be blocked specifically by the
drug vesamicol in isolated intact synaptic vesicles.
One of the major surprises in cholinergic neurobiology
was the discovery of the genomic relationship between
choline acetyltransferase and the vesicular acetylcholine
transporter. Both genetic functions are arranged as a gene
complex in all species so far examined (i.e. nematodes,
Drosophila, rats, mice and humans). In nematodes and
Drosophila, the coding regions of the vesicular acetylcho-
line transporter are nested entirely within the first intron of
the choline acetyltransferase gene and a common sequence
is contained in each specific transcript. The specific
transcripts are thought to arise by posttranscriptional
RNA processing. Vertebrates appear to have specific
transcripts with both shared and unique sequences. The
latter are thought to arise from alternative promoter usage.
Common
Transferase-specific exons
regulatory
region
Shared exon Transporter-specific exon
Figure 3 Organization of the cholinergic gene locus. The vesicular
transporter and choline acetyltransferase share a common exon
and transcriptional regulatory region.
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Acetylcholine
The conservation and organization of these two distinct
but related genetic functions may be related to coordinate
control of expression at the transcriptional level. The
cholinergic gene locus, shown schematically in Figure 3,
thus has properties of a eukaryotic operon, ensuring that
both choline acetyltransferase and the vesicular acetylcho-
line transporter are expressed in the same cells at the same
time.
Diseases Associated with Cholinergic
Dysfunction
The best understood human diseases of cholinergic
dysfunction are disorders of skeletal neuromuscular
transmission. Myasthenia gravis is characterized by
episodic weakness in muscles primarily innervated by the
cholinergic cranial motor neurons. The disease is caused
by an autoimmune attack on postsynaptic cholinergic
receptors, thus resulting in an effective block of neuro-
transmission. Current treatments include use of acetylcho-
linesterase inhibitors or procedures to reduce the level of
antireceptor antibodies. Amyotrophic lateral sclerosis is
characterized by degenerating spinal cord anterior horn
cell motor neurons, leading to progressive muscular
weakness and eventual atrophy. A familial form of this
condition has recently been proposed to be due to defects in
the superoxide dismutase gene. Eaton–Lambert syn-
drome, a presynaptic neuromuscular disorder, results from
impaired acetylcholine release at nerve terminals.
Several CNS neurodegenerative diseases also have
cholinergic dysfunction. Alzheimer disease is a common
age-related progressive degenerative disorder of the CNS
that results in impaired thinking, memory and behaviour.
The number of cholinergic neurons in the basal forebrain
(basal nucleus, diagonal band of Broca and medial septum)
is substantially lower in patients with Alzheimer disease
and the loss of these neurons may be related to the impaired
cognitive functions. Several other types of CNS neurode-
generative disorders, such as Parkinson disease and
Huntington disease, have aspects of cholinergic dysfunc-
tion. Although cholinergic neurons are not the primary
type of degenerating cells in these diseases, the cholinergic
symptoms are believed to result from an imbalance in
cholinergic neurotransmission thought to be caused by a
loss of inhibitory control.
Although not technically a disease, smoking is a primary
public health problem with a strong cholinergic compo-
nent. Nicotine in tobacco smoke is believed to be
an addictive stimulus for certain types of central choliner-
gic receptors, which reinforces the pleasurable aspects
of smoking in spite of the obvious health-threatening
consequences. Other cholinergic-related health problems
involve the deliberate or accidental exposure to
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 Acetylcholine

anticholinergic drugs or chemicals primarily used as
insecticides.
Acetylcholinesterase Inhibitors: Use as
Insecticides, in Chemical Warfare and as
Therapeutic Agents
Inhibitors of acetylcholinesterase activity are often termed
anticholinergics and include a variety of compounds that
reversibly or irreversibly inhibit enzyme activity. Some
representative structures are shown in Figure 4. Since
acetylcholine is ordinarily removed rapidly from choliner-
gic synapses by esterase hydrolysis, the actions of these
inhibitors can all be related to the persistence of
neurotransmitter at the various effector organs, neuro-
muscular junctions or in the CNS. The action of most
naturally occurring plant alkaloid inhibitors of acetylcho-
linesterase is easily reversed by high concentrations of
acetylcholine; these inhibitors include such prototypical
structures as physostigmine (eserine) or neostigmine which
are loosely bound to the active site of the enzyme. Another
class of inhibitors includes the highly toxic irreversible
organophosphates such as diisopropyl fluorophosphate.
These irreversible inhibitors were first used as effective
insecticides (i.e. parathion and malathion) and are thought
to work essentially by preventing termination of choliner-
gic neurotransmission (i.e. continual stimulation of
cholinergic receptors).
Certain members of this class of compounds have also
been developed as chemical warfare agents (i.e. Tabun,
Sarin, Soman and VX). The organophosphate inhibitors
irreversibly phosphorylate a serine residue within
Reversible inhibitors
CH3
O C N CH3
O H CH3
N N
CH3 CH3
Physostigmine
Irreversible inhibitors
CH3
H3 CH2 S CH3
CH3 CH O O P O
P H3 CH2
O NO2
CH3 CH O F
CH3
the active site of acetylcholinesterase that is essential
for enzyme activity. The more toxic members of the
organophosphates class of inhibitors undergo secon-
dary chemical reactions when covalently attached to
acetylcholinesterase, termed ‘ageing’. Aged enzyme is
impossible to reactivate and thus recovery from organo-
phosphate poisoning often requires removal of the
organophosphate and synthesis of new enzyme. Symptoms
of acute organophosphate poisoning can include excessive
salivation and lacrimation, digestive system disturbances,
muscle fasciculation and weakness, constriction of the
pupils and depressed levels of consciousness or seizures.
Treatment involves respiratory management and admin-
istration of atropine, which acts primarily by blocking
cholinergic transmission at muscarinic type acetylcholine
receptors.
Therapeutic uses of acetylcholine esterase inhibitors
include treatment for certain ocular conditions (i.e. to
reduce intraocular pressure), enhancement of gastric
contractions and/or intestinal motility, and enhancement
of skeletal neuromuscular transmission (i.e. in the treat-
ment of hypofunction of cholinergic neuromuscular
junctions in conditions such as myasthenia gravis). More
recent experimental studies are employing reversible
inhibitors that cross the blood–brain barrier to enhance
central cholinergic transmission in Alzheimer disease.
Summary
Acetylcholine is a versatile neurotransmitter substance in
the nervous systems of all animals. The actions of
acetylcholine can be both inhibitory and excitatory, and
examples of cholinergic synaptic transmission are seen in
both the central and peripheral nervous system. The gene
products that synthesize (choline acetyltransferase), pack-
age (the vesicular acetylcholine transporter), inactivate
(acetylcholinesterase) and receive (muscarinic and nicoti-
nic receptors) cholinergic signals have all been cloned and
CH3 O
CH3 characterized in a variety of different species. Precise
N O C N molecular information is not yet available for the plasma
CH3
CH3 membrane choline transporter, which also participates in
the cholinergic cycle. A number of human diseases are
known which have various presynaptic and/or postsynap-
Neostigmine
tic defects in cholinergic neurotransmission. Acetylcholi-
nesterase is a primary target of clinically useful drugs as
well as toxic insecticides and chemical warfare agents.
Drugs that block the action of acetylcholine at receptors
CH O
CH3 P are also used clinically and several toxins have similar
CH3 F actions.

Diisopropyl Parathion Sarin

fluorophosphate [O,O-diethyl O-(4-
nitrophenyl)-phosphate];
(isopropyl
methylphosphono-
Further Reading
insecticide fluoridate);
Bardin PG, van Eeden SF, Moolman JA, Foden AP and Joubert JR
nerve gas
(1994) Organophosphate and carbamate poisoning. Archives of
Figure 4 Some common types of acetylcholinesterase inhibitors. Internal Medicine 154: 1433–1441.

6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net


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