Download Acetylcholine Acetylcholine IUPAC name[hide] 2-Acetoxy

Acetylcholine
Acetylcholine
IUPAC name[hide]
2-Acetoxy-N,N,N-trimethylethanaminium
Properties
Molecular formula
C7H16NO2+
The chemical compound acetylcholine (often abbreviated ACh) is a neurotransmitter in both the peripheral
nervous system (PNS) and central nervous system (CNS) in many organisms including humans. Acetylcholine
is one of many neurotransmitters in the autonomic nervous system (ANS) and the only neurotransmitter used in
the motor division of the somatic nervous system. (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.[1]
History
Acetylcholine (ACh) was first identified in the year 1914 by Henry Hallett Dale for its actions on heart tissue. It
was confirmed as a neurotransmitter by Otto Loewi, who initially gave it the nameVagusstoff because it was
released from the vagus nerve. Both received the 1936 Nobel Prize in Physiology or Medicine for their work.
Acetylcholine was also the first neurotransmitter to be identified.
Chemistry
Acetylcholine is an ester of acetic acid and choline with chemical formula CH3COOCH2CH2N+(CH3)3. This
structure is reflected in the systematic name, 2-acetoxy-N,N,N-trimethylethanaminium. Its receptors have very
high binding constants.
Function
Acetylcholine
Abbreviation
ACh
Sources
many
Targets
many
Receptors
nicotinic; muscarinic
Agonists
nicotine, physostigmine
Antagonists
curare, atropine
Precursor
choline
Synthesizing enzyme
Choline acetyltransferase(ChAT)
Metabolizing enzyme
Acetylcholinesterase(AChE)
Acetylcholine has functions both in the peripheral nervous system (PNS) and in the central nervous
system (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 system, acetylcholine activates muscles, and is a major neurotransmitter in the
autonomic nervous system. When acetylcholine binds to acetylcholine receptors on skeletal muscle fibers, it
opens ligand-gated sodium channels in the cell membrane. 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
muscle fibers.
In the autonomic nervous system, acetylcholine is released in the following sites:

all pre- and post-ganglionic parasympathetic neurons

all preganglionic sympathetic neurons

preganglionic sympathetic fibers to suprarenal medulla, the modified sympathetic ganglion; on
stimulation by acetylcholine, the suprarenal medulla releases epinephrine and norepinephrine

some postganglionic sympathetic fibers

pseudomotor neurons to sweat glands.
In the central nervous system
Micrograph of the nucleus basalis (of Meynert), which produces acetylcholine in the CNS. LFB-HE stain.
In the central nervous system, ACh has a variety of effects as a neuromodulator upon plasticity, arousal
and reward. ACh has an important role in the enhancement of sensory perceptions when we wake up[2] and in
sustaining attention.[3]
Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be plausibly
associated with the memory deficits associated withAlzheimer's disease.[4] ACh has also been shown to be the
most important inducer of REM sleep.[citation needed]
Pathways
There are three ACh pathways in the CNS.[citation needed]

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 forebrain that projects axons to many areas of the brain. In the brainstem it originates
from the Pedunculopontine nucleus and dorsolateral tegmental nuclei collectively known as the mesopontine
tegmentum area or pontomesencephalotegmental complex.[5][6] 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, locus ceruleus, raphe nucleus, lateral reticular nucleus and inferior
olive.[6] It also projects to the thalamus, tectum, basal ganglia and basal forebrain.[5]

Basal optic nucleus of Meynert acts mainly on M1 receptors in the neocortex.

Medial septal nucleus acts mainly on M1 receptors in the hippocampus and neocortex.
In addition, ACh acts as an important "internal" transmitter in the striatum, which is part of the basal ganglia. 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 plasticity, specifically in learning and short-term memory.
Acetylcholine has been shown to enhance the amplitude of synaptic potentials following long-term
potentiation in many regions, including the dentate gyrus, CA1, piriform cortex, and neocortex. This effect most
likely occurs either through enhancing currents through NMDA receptors or indirectly by
suppressing adaptation. The suppression of adaptation has been shown in brain slices of regions
CA1, cingulate cortex, and piriform cortex, as well as in vivo in cat somatosensory and motor cortex by
decreasing the conductance of voltage-dependent M currents and Ca2+-dependent K+currents.[citation needed]
Excitability and inhibition
Acetylcholine also has other effects on neurons. One effect is to cause a slow depolarization[citation needed] by
blocking a tonically-active K+ current, which increases neuronal excitability. Alternatively, acetylcholine can
activate non-specific cation conductances to directly excite neurons.[7] An effect upon postsynaptic M4muscarinic ACh receptors is to open inward-rectifier potassium ion channel(Kir) and cause inhibition.[8] 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.[9] 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.[10] 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.[11]
In the cerebral cortex, tonic ACh inhibits layer 4 medium spiny neurons, the main targets of thalamocortical
inputs while exciting pyramidal cells in layers 2/3 and layer 5.[8] 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 layerspecific effects of ACh might function to improve the signal noise ratio of cortical processing. [8] 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.[12]
Another theory[citation needed] interprets acetylcholine neuromodulation in the neocortex as modulating the estimate
of expected uncertainty, acting counter to norepinephrine (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 neurons by the enzyme choline acetyltransferase from the
compounds choline and acetyl-CoA.
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, thus causing paralysis of the muscles needed for
breathing and stopping the beating of the heart.
Receptors
Main article: Acetylcholine receptor
There are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR)
and muscarinic acetylcholine receptors (mAChR). They are named for the ligands used to activate the
receptors.
Nicotinic
Nicotinic AChRs are ionotropic receptors permeable to sodium, potassium, and chloride ions. They are
stimulated by nicotine and acetylcholine. They are of two main types, muscle type and neuronal type. The
former can be selectively blocked by curare and the latter by hexamethonium. The main location of nicotinic
AChRs is on muscle end plates, autonomic ganglia (both sympathetic and parasympathetic), and in the
CNS.[13]
Myasthenia gravis
The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body
inappropriately produces antibodies 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 junction.
Muscarinic
Muscarinic receptors are metabotropic, and affect neurons over a longer time frame. They are stimulated
by muscarine and acetylcholine, and blocked by atropine. 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 nightshade 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 cataract surgery to produce rapid constriction of the pupil. It must be administered intraocularly
because corneal cholinesterase 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 mydriasis (dilation of the
pupil), in cardiopulmonary resuscitation 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, 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 gravis and Alzheimer's disease.
Alzheimer's disease
Since α4β2 AchRs are reduced in Alzheimer's disease, Drugs that inhibit acetylcholinesterase,
e.g. galanthamine (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[14]

Acetylcholine itself

Bethanechol

Carbachol

Cevimeline

Muscarine

Nicotine

Pilocarpine

Suberylcholine

Suxamethonium
Cholinesterase inhibitors
Main article: Cholinesterase inhibitors
Most indirect acting ACh receptor agonists work by inhibiting the enzyme acetylcholinesterase. 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 agents (Sarin and VX nerve gas) or pesticides(organophosphates and
the carbamates). In clinical use, they are administered 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).
Reversible
The following substances reversibly inhibit the enzyme acetylcholinesterase (which breaks down acetylcholine),
thereby increasing acetylcholine levels.


Many medications in Alzheimer's disease

Donepezil

Galantamine

Rivastigmine

Tacrine
Edrophonium (differs myasthenic and cholinergic crisis)

Neostigmine (in myasthenia gravis)

Physostigmine (in glaucoma and anticholinergic drug overdoses)

Pyridostigmine (in myasthenia gravis

Carbamate insecticides (e.g., Aldicarb)

Huperzine A
Irreversible
Semi-permanently inhibit the enzyme acetylcholinesterase.

Echothiophate

Isofluorophate

Organophosphate Insecticides (Malathion, Parathion, Azinphos methyl, Chlorpyrifos, among others)

Organophosphate-containing nerve agents (e.g., Sarin, VX)
Victims of organophosphate-containing nerve agents commonly die of suffocation as they cannot relax
their diaphragm.
Reactivation of acetylcholine esterase

Pralidoxime
ACh receptor antagonists
Antimuscarinic agents

Atropine

Ipratropium

Scopolamine

Tiotropium
Ganglionic blockers

Mecamylamine

Hexamethonium

Nicotine (in high doses)

Trimethaphan
Neuromuscular blockers

Atracurium

Cisatracurium

Doxacurium

Metocurine

Mivacurium

Pancuronium

Rocuronium

Succinylcholine

Tubocurarine

Vecuronium

Hemicholine
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
Botulin acts by suppressing the release of acetylcholine; where the venom from a black widow spider (alphalatrotoxin) has the reverse effect.