Acetylcholine (ACh) is an
organic chemical
In chemistry, organic compounds are generally any chemical compounds that contain carbon- hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. T ...
that functions in the brain and body of many types of animals (including humans) as a
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neu ...
.
Its name is derived from its chemical structure: it is an
ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...
of
acetic acid and
choline. Parts in the body that use or are affected by acetylcholine are referred to as
cholinergic. Substances that increase or decrease the overall activity of the cholinergic system are called
cholinergics and
anticholinergics, respectively.
Acetylcholine is the neurotransmitter used at the
neuromuscular junction—in other words, it is the chemical that
motor neurons of the nervous system release in order to activate muscles. This property means that drugs that affect cholinergic systems can have very dangerous effects ranging from paralysis to convulsions. Acetylcholine is also a neurotransmitter in the
autonomic nervous system, both as an internal transmitter for the
sympathetic nervous system and as the final product released by the
parasympathetic nervous system.
Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system.
In the brain, acetylcholine functions as a
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neu ...
and as a
neuromodulator. The brain contains a number of cholinergic areas, each with distinct functions; such as playing an important role in arousal, attention, memory and motivation.
Acetylcholine has also been found in cells of non-neural origins as well as microbes. Recently, enzymes related to its synthesis, degradation and cellular uptake have been traced back to early origins of unicellular eukaryotes.
The protist pathogen ''Acanthamoeba'' spp. has shown evidence of the presence of ACh, which provides growth and proliferative signals via a membrane located M1-muscarinic receptor homolog.
Partly because of its muscle-activating function, but also because of its functions in the autonomic nervous system and brain, many important drugs exert their effects by altering cholinergic transmission. Numerous venoms and toxins produced by plants, animals, and bacteria, as well as chemical
nerve agents such as
Sarin, cause harm by inactivating or hyperactivating muscles through their influences on the neuromuscular junction. Drugs that act on
muscarinic acetylcholine receptor
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end- ...
s, such as
atropine, can be poisonous in large quantities, but in smaller doses they are commonly used to treat certain heart conditions and eye problems.
Scopolamine, which acts mainly on muscarinic receptors in the brain, can cause
delirium,
hallucinations, and
amnesia. The addictive qualities of
nicotine
Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and '' Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is use ...
are derived from its effects on
nicotinic acetylcholine receptors in the brain.
Chemistry
Acetylcholine is a
choline molecule that has been
acetylated at the
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
atom. Because of the charged
ammonium group, acetylcholine does not penetrate lipid membranes. Because of this, when the molecule is introduced externally, it remains in the extracellular space and at present it is considered that the molecule does not pass through the blood–brain barrier.
Biochemistry
Acetylcholine is synthesized in certain
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s by the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
choline acetyltransferase
Choline acetyltransferase (commonly abbreviated as ChAT, but sometimes CAT) is a transferase enzyme responsible for the synthesis of the neurotransmitter acetylcholine. ChAT catalyzes the transfer of an acetyl group from the coenzyme acetyl-Co ...
from the compounds
choline and
acetyl-CoA. Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area is the nucleus basalis of Meynert in the basal forebrain.
The enzyme
acetylcholinesterase converts acetylcholine into the inactive
metabolites choline and
acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain
neurotoxins work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at the
neuromuscular junction, causing paralysis of the muscles needed for breathing and stopping the beating of the heart.
Functions
Acetylcholine functions in both the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS) and the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brai ...
(PNS). In the CNS, cholinergic projections from the
basal forebrain to the
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...
and
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...
support the
cognitive functions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system.
Cellular effects
Like many other biologically active substances, acetylcholine exerts its effects by binding to and activating
receptors located on the surface of cells. There are two main classes of acetylcholine receptor,
nicotinic and
muscarinic. They are named for chemicals that can selectively activate each type of receptor without activating the other:
muscarine is a compound found in the mushroom ''
Amanita muscaria'';
nicotine
Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and '' Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is use ...
is found in tobacco.
Nicotinic acetylcholine receptors are
ligand-gated ion channels permeable to
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...
,
potassium
Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmos ...
, and
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
ions. In other words, they are ion channels embedded in cell membranes, capable of switching from a closed to an open state when acetylcholine binds to them; in the open state they allow ions to pass through. Nicotinic receptors come in two main types, known as muscle-type and neuronal-type. The muscle-type can be selectively blocked by
curare, the neuronal-type by
hexamethonium
Hexamethonium is a non-depolarising ganglionic blocker, a nicotinic (nAChR) receptor antagonist that acts in autonomic ganglia by binding mostly in or on the nAChR receptor, and not the acetylcholine binding site itself. It does not have any ef ...
. The main location of muscle-type receptors is on muscle cells, as described in more detail below. Neuronal-type receptors are located in autonomic ganglia (both sympathetic and parasympathetic), and in the central nervous system.
Muscarinic acetylcholine receptor
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end- ...
s have a more complex mechanism, and affect target cells over a longer time frame. In mammals, five subtypes of muscarinic receptors have been identified, labeled M1 through M5. All of them function as
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s, meaning that they exert their effects via a
second messenger system. The M1, M3, and M5 subtypes are
Gq-coupled; they increase intracellular levels of
IP3 and
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
by activating
phospholipase C. Their effect on target cells is usually excitatory. The M2 and M4 subtypes are
Gi/Go-coupled; they decrease intracellular levels of
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
by inhibiting
adenylate cyclase. Their effect on target cells is usually inhibitory. Muscarinic acetylcholine receptors are found in both the central nervous system and the peripheral nervous system of the heart, lungs, upper gastrointestinal tract, and sweat glands.
Neuromuscular junction
Acetylcholine is the substance the nervous system uses to activate
skeletal muscles, a kind of striated muscle. These are the muscles used for all types of voluntary movement, in contrast to
smooth muscle tissue, which is involved in a range of involuntary activities such as movement of food through the gastrointestinal tract and constriction of blood vessels. Skeletal muscles are directly controlled by
motor neurons located in the
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
or, in a few cases, the
brainstem. These motor neurons send their
axons through
motor nerves, from which they emerge to connect to muscle fibers at a special type of
synapse called the
neuromuscular junction.
When a motor neuron generates an
action potential
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells ...
, it travels rapidly along the nerve until it reaches the neuromuscular junction, where it initiates an electrochemical process that causes acetylcholine to be released into the space between the presynaptic terminal and the muscle fiber. The acetylcholine molecules then bind to nicotinic ion-channel receptors on the muscle cell membrane, causing the ion channels to open. Sodium ions then flow into the muscle cell, initiating a sequence of steps that finally produce
muscle contraction
Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such a ...
.
Factors that decrease release of acetylcholine (and thereby affecting
P-type calcium channels):
#
Antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and preventio ...
(
clindamycin,
polymyxin)
# Magnesium: antagonizes P-type calcium channels
#
Hypocalcemia
#
Anticonvulsants
#
Diuretic
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...
s (
furosemide
Furosemide is a loop diuretic medication used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It may also be used for the treatment of high blood pressure. It can be taken by injection into a vein or by mo ...
)
#
Eaton-Lambert syndrome: inhibits P-type calcium channels
# Myasthenia gravis
#
Botulinum toxin: inhibits SNARE proteins
Calcium channel blockers (nifedipine, diltiazem) do not affect P-channels. These drugs affect
L-type calcium channels.
Autonomic nervous system
The
autonomic nervous system controls a wide range of involuntary and unconscious body functions. Its main branches are the
sympathetic nervous system and
parasympathetic nervous system. Broadly speaking, the function of the sympathetic nervous system is to mobilize the body for action; the phrase often invoked to describe it is
fight-or-flight
The fight-or-flight or the fight-flight-or-freeze response (also called hyperarousal or the acute stress response) is a physiological reaction that occurs in response to a perceived harmful event, attack, or threat to survival. It was first des ...
. The function of the parasympathetic nervous system is to put the body in a state conducive to rest, regeneration, digestion, and reproduction; the phrase often invoked to describe it is "rest and digest" or "feed and breed". Both of these aforementioned systems use acetylcholine, but in different ways.
At a schematic level, the sympathetic and parasympathetic nervous systems are both organized in essentially the same way: preganglionic neurons in the central nervous system send projections to neurons located in autonomic ganglia, which send output projections to virtually every tissue of the body. In both branches the internal connections, the projections from the central nervous system to the autonomic ganglia, use acetylcholine as a neurotransmitter to innervate (or excite) ganglia neurons. In the parasympathetic nervous system the output connections, the projections from ganglion neurons to tissues that don't belong to the nervous system, also release acetylcholine but act on muscarinic receptors. In the sympathetic nervous system the output connections mainly release
noradrenaline, although acetylcholine is released at a few points, such as the
sudomotor innervation of the sweat glands.
Direct vascular effects
Acetylcholine in the
serum
Serum may refer to:
* Serum (blood), plasma from which the clotting proteins have been removed
**Antiserum, blood serum with specific antibodies for passive immunity
* Serous fluid, any clear bodily fluid
*Truth serum, a drug that is likely to mak ...
exerts a direct effect on
vascular tone
Vascular resistance is the resistance that must be overcome to push blood through the circulatory system and create flow. The resistance offered by the systemic circulation is known as the systemic vascular resistance (SVR) or may sometimes be ...
by binding to
muscarinic receptor
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rec ...
s present on vascular
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
. These cells respond by increasing production of
nitric oxide, which signals the surrounding smooth muscle to relax, leading to
vasodilation.
Central nervous system
In the central nervous system, ACh has a variety of effects on plasticity, arousal and
reward. ACh has an important role in the enhancement of alertness when we wake up,
in sustaining attention
and in learning and memory.
Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be associated with the memory deficits associated with
Alzheimer's disease.
ACh has also been shown to promote
REM
Rem or REM may refer to:
Music
* R.E.M., an American rock band
* ''R.E.M.'' (EP), by Green
* "R.E.M." (song), by Ariana Grande
Organizations
* La République En Marche!, a French centrist political party
* Reichserziehungsministerium, in Nazi ...
sleep.
In the brainstem acetylcholine originates from the
Pedunculopontine nucleus
The pedunculopontine nucleus (PPN) or pedunculopontine tegmental nucleus (PPT or PPTg) is a collection of neurons located in the upper pons in the brainstem. It lies caudal to the substantia nigra and adjacent to the superior cerebellar pedunc ...
and
laterodorsal tegmental nucleus
The laterodorsal tegmental nucleus (or lateroposterior tegmental nucleus) is a nucleus situated in the brainstem, spanning the midbrain tegmentum and the pontine tegmentum. Its location is one-third of the way from the pedunculopontine nucleus ...
collectively known as the meso
pontine tegmentum area or pontomesencephalotegmental complex.
In the basal forebrain, it originates from the
basal nucleus of Meynert and medial
septal nucleus:
* The ''pontomesencephalotegmental complex'' acts mainly on
M1 receptors in the
brainstem, deep
cerebellar nuclei,
pontine nuclei,
locus coeruleus
The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system.
The locus coer ...
,
raphe nucleus,
lateral reticular nucleus
The lateral reticular nucleus, of the lateral funiculus, can be divided into three subnuclei, the parvocellular, magnocellular and the ''subtrigeminal''. As is typical of the reticular formation, none of these are very distinct subnuclei, but rat ...
and
inferior olive.
It also projects to the
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...
,
tectum,
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an ext ...
and
basal forebrain.
*
Basal nucleus of Meynert acts mainly on
M1 receptors in the
neocortex.
* Medial
septal nucleus acts mainly on
M1 receptors in the
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...
and parts of the
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...
.
In addition, ACh acts as an important internal transmitter in the
striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives gluta ...
, which is part of the
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an ext ...
. It is released by cholinergic
interneurons. In humans, non-human primates and rodents, these interneurons respond to salient environmental stimuli with responses that are temporally aligned with the responses of dopaminergic neurons of the
substantia nigra
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra ap ...
.
Memory
Acetylcholine has been implicated in
learning and
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remember ...
in several ways. The anticholinergic drug,
scopolamine, impairs acquisition of new information in humans
and animals.
In animals, disruption of the supply of acetylcholine to the
neocortex impairs the learning of simple discrimination tasks, comparable to the acquisition of factual information
and disruption of the supply of acetylcholine to the
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...
and adjacent cortical areas produces forgetfulness, comparable to
anterograde amnesia in humans.
Diseases and disorders
Myasthenia gravis
The disease
myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...
against acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission. Over time, the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine, physostigmine, or primarily pyridostigmine) are effective in treating the symptoms of this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the synaptic cleft (the space between nerve and muscle).
Pharmacology
Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it. Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme
acetylcholinesterase, which degrades the receptor ligand. Agonists increase the level of receptor activation; antagonists reduce it.
Acetylcholine itself does not have therapeutic value as a drug for intravenous administration because of its multi-faceted action (non-selective) and rapid inactivation by cholinesterase. However, it is used in the form of eye drops to cause constriction of the pupil during cataract surgery, which facilitates quick post-operational recovery.
Nicotinic receptors
Nicotine binds to and activates
nicotinic acetylcholine receptors, mimicking the effect of acetylcholine at these receptors. ACh opens a Na
+ channel upon binding so that Na
+ flows into the cell. This causes a depolarization, and results in an excitatory post-synaptic potential. Thus, ACh is excitatory on skeletal muscle; the electrical response is fast and short-lived.
Curares are arrow poisons, which act at nicotinic receptors and have been used to develop clinically useful therapies.
Muscarinic receptors
Muscarinic receptors form
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
complexes in the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
s of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s and other cells.
Atropine is a non-selective competitive antagonist with Acetylcholine at muscarinic receptors.
Cholinesterase inhibitors
Many ACh receptor agonists work indirectly by inhibiting the enzyme
acetylcholinesterase. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system, which can result in fatal convulsions if the dose is high.
They are examples of
enzyme inhibitors, and increase the action of acetylcholine by delaying its degradation; some have been used as
nerve agents (
Sarin and
VX nerve gas) or
pesticides (
organophosphates and the
carbamates
In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formall ...
). Many toxins and venoms produced by plants and animals also contain cholinesterase inhibitors. In clinical use, they are administered in low doses to reverse the action of
muscle relaxants, to treat
myasthenia gravis, and to treat symptoms of
Alzheimer's disease (
rivastigmine, which increases cholinergic activity in the brain).
Synthesis inhibitors
Organic
mercurial compounds, such as
methylmercury, have a high affinity for
sulfhydryl groups, which causes dysfunction of the enzyme choline acetyltransferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function.
Release inhibitors
Botulinum toxin (Botox) acts by suppressing the release of acetylcholine, whereas the venom from a
black widow spider
''Latrodectus'' is a broadly distributed genus of spiders with several species that are commonly known as the true widows. This group is composed of those often loosely called black widow spiders, brown widow spiders, and similar spiders. Howeve ...
(
alpha-latrotoxin
A latrotoxin is a high-molecular mass neurotoxin found in the venom of spiders of the genus ''Latrodectus'' (widow spiders) as well as at least one species of another genus in the same family, ''Steatoda nobilis''. Latrotoxins are the main active ...
) has the reverse effect. ACh inhibition causes
paralysis. When bitten by a
black widow spider
''Latrodectus'' is a broadly distributed genus of spiders with several species that are commonly known as the true widows. This group is composed of those often loosely called black widow spiders, brown widow spiders, and similar spiders. Howeve ...
, one experiences the wastage of ACh supplies and the muscles begin to contract. If and when the supply is depleted,
paralysis occurs.
Comparative biology and evolution
Acetylcholine is used by organisms in all domains of life for a variety of purposes. It is believed that choline, a precursor to acetylcholine, was used by single celled organisms billions of years ago for synthesizing cell membrane phospholipids.
Following the evolution of choline transporters, the abundance of intracellular choline paved the way for choline to become incorporated into other synthetic pathways, including acetylcholine production. Acetylcholine is used by bacteria, fungi, and a variety of other animals. Many of the uses of acetylcholine rely on its action on ion channels via GPCRs like membrane proteins.
The two major types of acetylcholine receptors, muscarinic and nicotinic receptors, have convergently evolved to be responsive to acetylcholine. This means that rather than having evolved from a common homolog, these receptors evolved from separate receptor families. It is estimated that the
nicotinic receptor family dates back longer than 2.5 billion years.
Likewise, muscarinic receptors are thought to have diverged from other GPCRs at least 0.5 billion years ago. Both of these receptor groups have evolved numerous subtypes with unique ligand affinities and signaling mechanisms. The diversity of the receptor types enables acetylcholine to create varying responses depending on which receptor types are activated, and allow for acetylcholine to dynamically regulate physiological processes. ACh receptors are related to
5-HT3
The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs) and therefore differs structurally and functionally from all other 5-HT receptors (5-hydroxytryptamine, or serotonin receptors) which are G protein-coup ...
(
serotonin),
GABA, and
Glycine receptors, both in sequence and structure, strongly suggesting that they have a common evolutionary origin.
History
In 1867,
Adolf von Baeyer
Johann Friedrich Wilhelm Adolf von Baeyer (; 31 October 1835 – 20 August 1917) was a German chemist who synthesised indigo and developed a nomenclature for cyclic compounds (that was subsequently extended and adopted as part of the IUPAC org ...
resolved the structures of
choline and acetylcholine and synthetized them both, referring to the latter as "''acetylneurin''" in the study.
Choline is a precursor for acetylcholine. This is why
Frederick Walker Mott and
William Dobinson Halliburton
William Dobinson Halliburton FRS (21 June 1860, in Middlesex – 21 May 1931, in Exeter) was a British physiologist, noted for being one of the founders of the science of biochemistry.
William was one of four children (three sisters) born to Th ...
noted in 1899 that choline injections decreased the blood pressure of animals.
[ Acetylcholine was first noted to be biologically active in 1906, when Reid Hunt (1870–1948) and René de M. Taveau found that it decreased ]blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure ...
in exceptionally tiny doses.[
In 1914, Arthur J. Ewins was the first to extract acetylcholine from nature. He identified it as the blood pressure decreasing contaminant from some '' Claviceps purpurea'' ergot extracts, by the request of ]Henry Hallett Dale
Sir Henry Hallett Dale (9 June 1875 – 23 July 1968) was an English pharmacologist and physiologist. For his study of acetylcholine as agent in the chemical transmission of nerve pulses (neurotransmission) he shared the 1936 Nobel Prize in Ph ...
.[ Later in 1914, Dale outlined the effects of acetylcholine at various types of peripheral synapses and also noted that it lowered the blood pressure of cats via ]subcutaneous injection
Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion.
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, c ...
s even at doses of one nanogram.[
The concept of ]neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neu ...
s was unknown until 1921, when Otto Loewi
Otto Loewi (; 3 June 1873 – 25 December 1961) was a German-born pharmacologist and psychobiologist who discovered the role of acetylcholine as an endogenous neurotransmitter. For his discovery he was awarded the Nobel Prize in Physiology or M ...
noted that the vagus nerve secreted a substance that inhibited the heart muscle whilst working as a professor in the University of Graz. He named it ''vagusstoff
Vagusstoff (literally translated from German as "Vagus Substance") refers to the substance released by stimulation of the vagus nerve which causes a reduction in the heart rate. Discovered in 1921 by physiologist Otto Loewi, ''vagusstoff'' was ...
'' ("vagus substance"), noted it to be a structural analog of choline and suspected it to be acetylcholine. In 1926, Loewi and E. Navratil deduced that the compound is probably acetylcholine, as vagusstoff and synthetic acetylcholine lost their activity in a similar manner when in contact with tissue lysate
Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bi ...
s that contained acetylcholine-degrading enzymes (now known to be cholinesterases). This conclusion was accepted widely. Later studies confirmed the function of acetylcholine as a neurotransmitter.
In 1936, H. H. Dale and O. Loewi shared the Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accordi ...
for their studies of acetylcholine and nerve impulses.[
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See also
* Ann Silver
* Acetylcholinesterase
* Neuromuscular junction
* Nicotinic acetylcholine receptor
* Muscarinic acetylcholine receptor
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end- ...
Specific references
General bibliography
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External links
Warning over combining common medicines for elderly
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Acetate esters
Choline esters
Cholinergics
Muscarinic agonists
Nicotinic agonists
Quaternary ammonium compounds
Ophthalmology drugs