The
chemical compoundA chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
acetylcholine (often abbreviated
ACh) is a
neurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in both the
peripheral nervous systemThe peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
(PNS) and
central nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) in many organisms including humans. Acetylcholine is one of many neurotransmitters in the
autonomic nervous systemThe autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
(ANS) and the only neurotransmitter used in the motor division of the
somatic nervous systemThe somatic nervous system is the part of the peripheral nervous system associated with the voluntary control of body movements via skeletal muscles...
(sensory neurons use glutamate and various peptides at their synapses). Acetylcholine is also the principal neurotransmitter in all autonomic ganglia.
Acetylcholine slows the heart rate when functioning as an inhibitory neurotransmitter. However, acetylcholine also behaves as an excitatory neurotransmitter at neuromuscular junctions.
History
Acetylcholine (ACh) was first identified in 1914 by
Henry Hallett DaleSir Henry Hallett Dale, OM, GBE, PRS was an English pharmacologist and physiologist. For his study of acetylcholine as agent in the chemical transmission of nerve impulses he shared the 1936 Nobel Prize in Physiology or Medicine with Otto Loewi.-Biography:Henry Hallett Dale was born in Islington,...
for its actions on heart tissue. It was confirmed as a neurotransmitter by
Otto LoewiOtto Loewi was a German born pharmacologist whose discovery of acetylcholine helped enhance medical therapy. The discovery earned for him the Nobel Prize in Physiology or Medicine in 1936 which he shared with Sir Henry Dale, whom he met in 1902 when spending some months in Ernest Starling's...
, who initially gave it the name
VagusstoffVagusstoff 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 the first confirmation of chemical synaptic transmission and the first neurotransmitter ever discovered...
because it was released from the
vagus nerveThe vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...
. Both received the 1936
Nobel Prize in Physiology or MedicineThe Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
for their work. Acetylcholine was also the first
neurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
to be identified.
Chemistry
Acetylcholine is an
esterEsters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
of
acetic acidAcetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
and
cholineCholine is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
with
chemical formulaA chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....
CH3COIn organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...
OOxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
CH
2CH
2NNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
+(CH
3)
3. This structure is reflected in the systematic name,
2-acetoxy-N,N,N-trimethylethanaminium. Its receptors have very high binding constants.
Function
Acetylcholine has functions both in the
peripheral nervous systemThe peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
(PNS) and in the
central nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) as a neuromodulator.
In the peripheral nervous system, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system.
In the central nervous system, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system, which tends to cause anti-excitatory actions.
In the peripheral nervous system
In the
peripheral nervous systemThe peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system.
When acetylcholine binds to
acetylcholine receptorAn acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
s on
skeletal muscleSkeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
fibers, it opens ligand-gated sodium channels in the
cell membraneThe cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Sodium ions then enter the muscle cell, initiating a sequence of steps that finally produce muscle contraction. Although acetylcholine induces contraction of skeletal muscle, it acts via a different type of receptor (muscarinic) to
inhibit contraction of
cardiac muscleCardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
fibers.
In the
autonomic nervous systemThe autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
, acetylcholine is released in the following sites:
- all pre- and post-ganglionic parasympathetic
The parasympathetic nervous system is one of the two main divisions of the autonomic nervous system . The ANS is responsible for regulation of internal organs and glands, which occurs unconsciously...
neurons
- all preganglionic sympathetic
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
neurons
- preganglionic sympathetic fibers to suprarenal medulla, the modified sympathetic ganglion; on stimulation by acetylcholine, the suprarenal medulla releases epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
and norepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
- some postganglionic sympathetic fibers
- pseudomotor neurons to sweat gland
Sweat glands, or sudoriferous glands, are small tubular structures of the skin that produce sweat. There are two kinds of sweat glands:...
s.
In the central nervous system
In the central nervous system, ACh has a variety of effects as a neuromodulator upon plasticity, arousal and
rewardIn neuroscience, the reward system is a collection of brain structures which attempts to regulate and control behavior by inducing pleasurable effects...
. ACh has an important role in the enhancement of sensory perceptions when we wake up and in sustaining attention.
Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be plausibly associated with the memory deficits associated with
Alzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
ACh has also been shown to promote REM sleep
Pathways
There are three ACh pathways in the CNS.
- Pons to thalamus and cortex
- Magnocellular forebrain nucleus to cortex
- Septohippocampal
Structure
Acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system from the brainstem and
basal forebrainThe basal forebrain is a collection of structures located ventrally to the striatum. It is considered to be the major cholinergic output of the central nervous system . It includes a group of structures that lie near the bottom of the front of the brain, including the nucleus basalis, diagonal band...
that projects axons to many areas of the brain. In the brainstem it originates from the
Pedunculopontine nucleusThe pedunculopontine nucleus is located in the brainstem, caudal to the substantia nigra and adjacent to the superior cerebellar peduncle. It has two divisions, one containing cholinergic neurons, the pars compacta, and one containing mostly glutamatergic neurons, the pars dissipata...
and dorsolateral tegmental nuclei collectively known as the meso
pontine tegmentumThe pontine tegmentum is a part of the pons of the brain involved in the initiation of REM sleep. It includes the pedunculopontine nucleus and the laterodorsal tegmental nucleus, among others, and is located near the raphe nucleus and the locus ceruleus....
area or pontomesencephalotegmental complex. In the basal forebrain, it originates from the basal optic nucleus of Meynert and medial septal nucleus:
- The pontomesencephalotegmental complex acts mainly on M1 receptors in the brainstem, deep cerebellar nuclei, pontine nuclei
The pontine nuclei are a part of the pons involved in motor activity. Corticopontine fibres carry information from the primary motor cortex to the ipsilateral pontine nucleus in the ventral pons, and the pontocerebellar projection then carries that information to the contralateral cerebellum via...
, locus ceruleusThe locus coeruleus , is a nucleus in the brainstem involved with physiological responses to stress and panic. It was discovered in the 18th century by Félix Vicq-d'Azyr....
, raphe nucleus, lateral reticular nucleusThe lateral reticular nucleus, of the 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 rather blurred distinctions between cell types and location...
and inferior olive. It also projects to the thalamusThe thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, tectum, basal gangliaThe basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
and basal forebrainThe basal forebrain is a collection of structures located ventrally to the striatum. It is considered to be the major cholinergic output of the central nervous system . It includes a group of structures that lie near the bottom of the front of the brain, including the nucleus basalis, diagonal band...
.
- Basal optic nucleus of Meynert acts mainly on M1 receptors in the neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
.
- Medial septal nucleus acts mainly on M1 receptors in the hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and neocortexThe neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
.
In addition, ACh acts as an important "internal" transmitter in the
striatumThe striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
, which is part of the
basal gangliaThe basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
. It is released by a large set of interneurons with smooth dendrites, known as
tonically active neurons or TANs.
Plasticity
ACh is involved with
synaptic plasticityIn neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
, specifically in
learningLearning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
and short-term memory.
Acetylcholine has been shown to enhance the amplitude of synaptic potentials following
long-term potentiationIn neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
in many regions, including the
dentate gyrusThe dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
, CA1,
piriform cortexIn anatomy of animals, the piriform cortex, or pyriform cortex is a region in the brain.-Anatomy and function:The piriform cortex is part of the rhinencephalon situated in the telencephalon....
, and
neocortexThe neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...
. This effect most likely occurs either through enhancing currents through
NMDAN-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
receptors or indirectly by suppressing
adaptationNeural adaptation or sensory adaptation is a change over time in the responsiveness of the sensory system to a constant stimulus. It is usually experienced as a change in the stimulus. For example, if one rests one's hand on a table, one immediately feels the table's surface on one's skin. Within a...
. The suppression of adaptation has been shown in brain slices of regions CA1,
cingulate cortexThe cingulate cortex is a part of the brain situated in the medial aspect of the cortex. It includes the cortex of the cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the cingulate sulcus...
, and piriform cortex, as well as
in vivoIn vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
in cat somatosensory and
motor cortexMotor cortex is a term that describes regions of the cerebral cortex involved in the planning, control, and execution of voluntary motor functions.-Anatomy of the motor cortex :The motor cortex can be divided into four main parts:...
by decreasing the conductance of voltage-dependent M currents and
Ca2+Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
-dependent
K+Potassium is an essential mineral macronutrient and is the main intracellular ion for all types of cells.It is important in maintaining fluid and electrolyte balance in the bodies of humans and animals....
currents.
Excitability and inhibition
Acetylcholine also has other effects on neurons. One effect is to cause a slow
depolarizationIn biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
by blocking a tonically-active K
+ current, which increases neuronal excitability. Alternatively, acetylcholine can activate non-specific cation conductances to directly excite neurons. An effect upon postsynaptic
M4-muscarinic ACh receptorThe muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 , is a protein that, in humans, is encoded by the CHRM4 gene.-Function:...
s is to open
inward-rectifier potassium ion channelInwardly rectifying potassium channels are a specific subset of potassium selective ion channels. To date, seven subfamilies have been identified in various mammalian cell types...
(K
ir) and cause inhibition. The influence of acetylcholine on specific neuron types can be dependent upon the duration of cholinergic stimulation. For instance, transient exposure to acetylcholine (up to several seconds) can inhibit cortical pyramidal neurons via M1 type muscarinic receptors that are linked to Gq-type G-protein alpha subunits. M1 receptor activation can induce calcium-release from intracellular stores, which then activate a calcium-activated potassium conductance which inhibits pyramidal neuron firing. On the other hand, tonic M1 receptor activation is strongly excitatory. Thus, ACh acting at one type of receptor can have multiple effects on the same postsynaptic neuron, depending on the duration of receptor activation. Recent experiments in behaving animals have demonstrated that cortical neurons indeed experience both transient and persistent changes in local acetylcholine levels during cue-detection behaviors.
In the cerebral cortex, tonic ACh inhibits layer 4
medium spiny neuronThe medium spiny neurons are a special type of inhibitory cells representing approximately 90% of the neurons within the corpus striatum of the basal ganglia. They play a key role in initiating and controlling movements of the body, limbs, and eyes....
s, the main targets of thalamocortical inputs while exciting
pyramidal cellPyramidal neurons are a type of neuron found in areas of the brain including cerebral cortex, the hippocampus, and in the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. Pyramidal neurons were first discovered and...
s in layers 2/3 and layer 5. This filters out weak sensory inputs in layer 4 and amplifies inputs that reach the layers 2/3 and layer L5 excitatory microcircuits. As a result, these layer-specific effects of ACh might function to improve the signal noise ratio of cortical processing. At the same time, acetylcholine acts through nicotinic receptors to excite certain groups of inhibitory interneurons in the cortex, which further dampen down cortical activity.
Another theory interprets acetylcholine neuromodulation in the neocortex as modulating the estimate of expected uncertainty, acting counter to
norepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(NE) signals for unexpected uncertainty. Both modulations would then decrease synaptic transition strength, but ACh would then be needed to counter the effects of NE in learning, a signal understood to be 'noisy'.
Synthesis and degradation
Acetylcholine is synthesized in certain
neuronA neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s by the
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
choline acetyltransferaseCholine acetyltransferase is an enzyme that is synthesized within the body of a neuron. It is then transferred to the nerve terminal via axoplasmic flow. The role of choline acetyltransferase is to join Acetyl-CoA to choline, resulting in the formation of the neurotransmitter acetylcholine...
from the compounds
cholineCholine is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
and
acetyl-CoAAcetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
.
The enzyme
acetylcholinesterase"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
converts acetylcholine into the inactive metabolites
cholineCholine is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
and
acetateAn acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...
. 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 junctionA neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
, thus causing paralysis of the muscles needed for breathing and stopping the beating of the heart.
Receptors
There are two main classes of acetylcholine receptor (AChR),
nicotinic acetylcholine receptorNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s (nAChR) and
muscarinic acetylcholine receptorMuscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s (mAChR). They are named for the
ligandsIn biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
used to activate the receptors.
Nicotinic
Nicotinic AChRsNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
are
ionotropic receptorsLigand-gated ion channels are one type of ionotropic receptor or channel-linked receptor. They are a group of transmembrane ion channels that are opened or closed in response to the binding of a chemical messenger , such as a neurotransmitter.The binding site of endogenous ligands on LGICs...
permeable to
sodiumSodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
,
potassiumPotassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
, and
chlorideThe chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
ions. They are stimulated by
nicotineNicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
and acetylcholine. They are of two main types, muscle type and neuronal type. The former can be selectively blocked by
curareCurare is a common name for various arrow poisons originating from South America. The three main types of curare are:* tubocurare...
and the latter by
hexamethoniumHexamethonium is a ganglionic blocker, a nicotinic nACh receptor antagonist that acts in autonomic ganglia by binding mostly in or on the NN receptor, and not the acetylcholine binding site itself...
. The main location of nicotinic AChRs is on
muscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
end plates, autonomic ganglia (both sympathetic and parasympathetic), and in the CNS.
Myasthenia gravis
The disease
myasthenia gravisMyasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces
antibodiesAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
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 this disorder. They allow endogenously-released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the
gap junctionA gap junction or nexus is a specialized intercellular connection between a multitude of animal cell-types. It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells....
.
Muscarinic
Muscarinic receptors are metabotropic, and affect neurons over a longer time frame. They are stimulated by
muscarineMuscarine, L--muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. Mushrooms in the genera Entoloma and Mycena have also been found to contain levels of muscarine which can be dangerous if ingested...
and acetylcholine, and blocked by
atropineAtropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
. Muscarinic receptors are found in both the central nervous system and the peripheral nervous system, in heart, lungs, upper GI tract and sweat glands. Extracts from the plant
Deadly nightshadeAtropa belladonna or Atropa bella-donna, commonly known as Belladonna, Devil's Berries, Death Cherries or Deadly Nightshade, is a perennial herbaceous plant in the family Solanaceae, native to Europe, North Africa, and Western Asia. The foliage and berries are extremely toxic, containing tropane...
included this compound (atropine), and the blocking of the muscarinic AChRs increases pupil size as used for attractiveness in many European cultures in the past. Now, ACh is sometimes used during
cataractA cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...
surgery to produce rapid constriction of the pupil. It must be administered intraocularly because
corneaThe cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
l
cholinesteraseIn biochemistry, cholinesterase is a family of enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.-Types:...
metabolizes topically-administered ACh before it can diffuse into the eye. It is sold by the trade name Miochol-E (CIBA Vision). Similar drugs are used to induce
mydriasisMydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
(dilation of the pupil), in
cardiopulmonary resuscitationCardiopulmonary resuscitation is an emergency procedure which is performed in an effort to manually preserve intact brain function until further measures are taken to restore spontaneous blood circulation and breathing in a person in cardiac arrest. It is indicated in those who are unresponsive...
and many other situations.
Drugs acting on the acetylcholine system
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.
ACh receptor agonists/antagonists
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"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
, which degrades the receptor ligand. Agonists increase the level of receptor activation, antagonists reduce it.
Associated disorders
ACh Receptor Agonists are used to treat
myasthenia gravisMyasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
and
Alzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
Alzheimer's disease
Since α4β2 AchRs are reduced in Alzheimer's disease, drugs that
inhibit acetylcholinesteraseAn acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...
, e.g. galantamine hydrobromide (a competitive and reversible cholinesterase inhibitor), are commonly used in the treatment of that disease.
Direct acting
These are drugs that mimic acetylcholine on the receptor. In low doses, they stimulate the receptors, in high they numb them due to depolarisation block.
- Acetyl l-carnitine
Acetyl-L-carnitine or ALCAR, is an acetylated form of L-carnitine. It is a dietary supplement and naturally occurs in plants and animals.- Biochemical Production and Action :ALCAR is an acetylated derivative of L-carnitine...
- Acetylcholine itself
- Bethanechol
Bethanechol is a parasympathomimetic choline carbamate that selectively stimulates muscarinic receptors without any effect on nicotinic receptors. Unlike acetylcholine, bethanechol is not hydrolyzed by cholinesterase and will therefore have a long duration of action. Bethanechol does not involve...
- Carbachol
Carbachol , also known as carbamylcholine, is a drug that binds and activates the acetylcholine receptor. Thus it is classified as a cholinergic agonist. It is primarily used for various ophthalmic purposes, such as for treating glaucoma, or for use during ophthalmic surgery...
- Cevimeline
- Muscarine
Muscarine, L--muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. Mushrooms in the genera Entoloma and Mycena have also been found to contain levels of muscarine which can be dangerous if ingested...
- Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
- Pilocarpine
Pilocarpine is a parasympathomimetic alkaloid obtained from the leaves of tropical American shrubs from the genus Pilocarpus. It is a non-selective muscarinic receptor agonist in the parasympathetic nervous system, which acts therapeutically at the muscarinic acetylcholine receptor M3 due to its...
- Suberylcholine
- Suxamethonium
Cholinesterase inhibitors
Most indirect acting ACh receptor agonists work by inhibiting the enzyme
acetylcholinesterase"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system.
They are examples of enzyme inhibitors, and increase the action of acetylcholine by delaying its degradation; some have been used as
nerve agentNerve agents are a class of phosphorus-containing organic chemicals that disrupt the mechanism by which nerves transfer messages to organs...
s (
SarinSarin, or GB, is an organophosphorus compound with the formula [2CHO]CH3PF. It is a colorless, odorless liquid, which is used as a chemical weapon. It has been classified as a weapon of mass destruction in UN Resolution 687...
and
VXVX, IUPAC name O-ethyl S-[2-ethyl] methylphosphonothioate, is an extremely toxic substance whose only application is in chemical warfare as a nerve agent. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations in UN Resolution 687...
nerve gas) or
pesticidePesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...
s (organophosphates and the carbamates). In clinical use, they are administered to reverse the action of
muscle relaxantA muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
s, to treat
myasthenia gravisMyasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
, and to treat symptoms of
Alzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(
rivastigmineRivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, which...
, which increases cholinergic activity in the brain).
Reversible
The following substances reversibly inhibit the enzyme
acetylcholinesterase"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
(which breaks down acetylcholine), thereby increasing acetylcholine levels.
- Many medications in Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
- Donepezil
Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer's disease. Common side effects include...
- Galantamine
Galantamine is used for the treatment of mild to moderate Alzheimer’s disease and various other memory impairments, in particular those of vascular origin...
- Rivastigmine
Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, which...
- Tacrine
Tacrine is a centrally acting anticholinesterase and indirect cholinergic agonist . It was the first centrally-acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the...
- Edrophonium
Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction...
(differs myasthenic and cholinergic crisisA cholinergic crisis is an over-stimulation at a neuromuscular junction due to an excess of acetylcholine , as of a result of the inactivity of the AChE enzyme, which normally breaks down acetylcholine. This is a consequence of some types of nerve gas,...
)
- Neostigmine
Neostigmine is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor.- Synthesis :Neostigmine was first synthesized by Aeschlimann and Reinert in 1931....
(commonly used to reverse the effect of neuromuscular blockers used in anaesthesia, or less often in myasthenia gravisMyasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
)
- Physostigmine
Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
(in glaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
and anticholinergicAn anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
drug overdoses)
- Pyridostigmine
Pyridostigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. Since it is a quaternary amine, it is poorly absorbed in the gut and does not cross the blood-brain barrier, except possibly in stressful conditions.-Mode of action:...
(in myasthenia gravisMyasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
- Carbamate
Carbamates are organic compounds derived from carbamic acid . A carbamate group, carbamate ester, and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes.-Synthesis:Carbamic acids are derived...
insecticides (e.g., AldicarbAldicarb is a carbamate insecticide which is the active substance in the pesticide Temik. It is effective against thrips, aphids, spider mites, lygus, fleahoppers, and leafminers, but is primarily used as a nematicide. Aldicarb is a cholinesterase inhibitor which prevents the breakdown of...
)
- Huperzine A
Huperzine A is a naturally occurring sesquiterpene alkaloid compound found in the plant firmoss Huperzia serrata. and in varying quantities in other Husperzia spp.including H. elmeri, H. carinat, H. aqualupian,...
Irreversible
Semi-permanently inhibit the enzyme acetylcholinesterase.
- Echothiophate
Echothiophate is a parasympathomimetic and a phosphorothioate. It is an acetylcholinesterase inhibitor.- Uses :It is used as an ocular antihypertensive in the treatment of chronic glaucoma and, in some cases, accommodative esotropia...
- Isofluorophate
- Organophosphate
An organophosphate is the general name for esters of phosphoric acid. Phosphates are probably the most pervasive organophosphorus compounds. Many of the most important biochemicals are organophosphates, including DNA and RNA as well as many cofactors that are essential for life...
Insecticides (MalathionMalathion is an organophosphate parasympathomimetic which binds irreversibly to cholinesterase. Malathion is an insecticide of relatively low human toxicity, however one recent study has shown that children with higher levels of organophosphate pesticide metabolites in their urine are more likely...
, ParathionParathion, also called parathion-ethyl or diethyl parathion, is an organophosphate compound. It is a potent insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms, including humans. Its use is banned or restricted in many...
, Azinphos methyl, ChlorpyrifosChlorpyrifos is a crystalline organophosphate insecticide that inhibits acetylcholinesterase and is used to control insect pests. It is known by many trade names...
, among others)
- Organophosphate-containing nerve agents (e.g., Sarin
Sarin, or GB, is an organophosphorus compound with the formula [2CHO]CH3PF. It is a colorless, odorless liquid, which is used as a chemical weapon. It has been classified as a weapon of mass destruction in UN Resolution 687...
, VXVX, IUPAC name O-ethyl S-[2-ethyl] methylphosphonothioate, is an extremely toxic substance whose only application is in chemical warfare as a nerve agent. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations in UN Resolution 687...
)
Victims of organophosphate-containing nerve agents commonly die of suffocation as they cannot relax their
diaphragmIn the anatomy of mammals, the thoracic diaphragm, or simply the diaphragm , is a sheet of internal skeletal muscle that extends across the bottom of the rib cage. The diaphragm separates the thoracic cavity from the abdominal cavity and performs an important function in respiration...
.
Ganglionic blockers
- Mecamylamine
Mecamylamine is a nonselective and noncompetitive antagonist of the nicotinic acetylcholine receptors that was introduced in the 1950s as an antihypertensive agent.- Uses :...
- Hexamethonium
Hexamethonium is a ganglionic blocker, a nicotinic nACh receptor antagonist that acts in autonomic ganglia by binding mostly in or on the NN receptor, and not the acetylcholine binding site itself...
- Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
(in high doses)
- Trimethaphan
Trimetaphan camsilate or trimethaphan camsylate , trade name Arfonad, is a drug that counteracts cholinergic transmission at the ganglion type of nicotinic receptors of the autonomic ganglia and therefore blocks both the sympathetic nervous system and the parasympathetic nervous system...
Neuromuscular blockers
- Atracurium
Atracurium besylate is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical...
- Cisatracurium
Cisatracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...
- Doxacurium
- Metocurine
Metocurine is a muscle relaxant through neuromuscular blockade.It is excreted entirely through the kidneys and therefore should not be used in patients with renal failure....
- Mivacurium
Mivacurium chloride is a short-duration non-depolarizing neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during...
- Pancuronium
Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :...
- Rocuronium
Rocuronium is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Introduced in 1994, rocuronium has...
- Succinylcholine
- Tubocurarine
Tubocurarine is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation...
- Vecuronium
Vecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...
- Hemicholine
Synthesis inhibitors
- Organic mercurial
Mercury is a chemical element with the symbol Hg and atomic number 80. It is also known as quicksilver or hydrargyrum...
compounds, such as methylmercuryMethylmercury is an organometallic cation with the formula . It is a bioaccumulative environmental toxicant.-Structure:...
, have a high affinity for sulfhydryl groupsIn organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
, which causes dysfunction of the enzyme choline acetyltransferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function.
Release inhibitors
- Botulin acts by suppressing the release of acetylcholine; where the venom from a black widow spider (alpha-latrotoxin
α-Latrotoxin can naturally be found in widow spiders of the genus Latrodectus. The most famous of those spiders are the black widows, Latrodectus mactans. The venom of widow spiders contains several protein toxins, called latrotoxins, which selectively target against either vertebrates, insects...
) has the reverse effect.
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