Dictionary:

acetylcholine

  (ə-sēt'l-kō'lēn')

Also from Answers.com... Cancer Treatments Learn about current and promising cancer treatments.

A white crystalline derivative of choline, C₇H₁₇NO₃, that is released at the ends of nerve fibers in the somatic and parasympathetic nervous systems and is involved in the transmission of nerve impulses in the body.

A naturally occurring quaternary ammonium cation ester, with the formula CH₃(O)COC₂H₄N(CH)₃⁺, that plays a prominent role in nervous system function. The great importance of acetylcholine derives from its role as a neurotransmitter for cholinergic neurons, which innervate many tissues, including smooth muscle and skeletal muscle, the heart, ganglia, and glands. The effect of stimulating a cholinergic nerve, for example, the contraction of skeletal muscle or the slowing of the heartbeat, results from the release of acetylcholine from the nerve endings.

Acetylcholine is synthesized at axon endings from acetyl coenzyme A and choline by the enzyme choline acetyltransferase, and is stored at each ending in hundreds of thousands of membrane-enclosed synaptic vesicles. When a nerve impulse reaches an axon ending, voltage-gated calcium channels in the axonal membrane open and calcium, which is extremely low inside the cell, enters the nerve ending. The increase in calcium-ion concentration causes hundreds of synaptic vesicles to fuse with the cell membrane and expel acetylcholine into the synaptic cleft (exocytosis). The acetylcholine released at a neuromuscular junction binds reversibly to acetylcholine receptors in the muscle end-plate membrane, a postsynaptic membrane that is separated from the nerve ending by a very short distance. The receptor is a cation channel which opens when two acetylcholine molecules are bound, allowing a sodium current to enter the muscle cell and depolarize the membrane. The resulting impulse indirectly causes the muscle to contract.

Acetylcholine must be rapidly removed from a synapse in order to restore it to its resting state. This is accomplished in part by diffusion but mainly by the enzyme acetylcholinesterase, which hydrolyzes acetylcholine.

Acetylcholinesterase is a very fast enzyme: one enzyme molecule can hydrolyze 10,000 molecules of acetylcholine in 1 s. Any substance that efficiently inhibits acetylcholinesterase will be extremely toxic.

Acetylcholine is a neurotransmitter released from nerve endings (terminals) in both the peripheral and the central nervous systems. It is synthesized within the nerve terminal from choline, taken up from the tissue fluid into the nerve ending by a specialized transport mechanism. The enzyme necessary for this synthesis (choline acetyltransferase) is formed in the nerve cell body and passes down the axon to its end, carried in the axoplasmic flow, the slow movement of intracellular substance (cytoplasm). Acetylcholine is stored in the nerve terminal, sequestered in small vesicles awaiting release.

When a nerve action potential reaches and invades the nerve terminal, a shower of acetylcholine vesicles is released into the junction (synapse) between the nerve terminal and the ‘effector’ cell which the nerve activates. This may be another nerve cell or a muscle or gland cell. Thus electrical signals are converted to chemical signals, allowing messages to be passed between nerve cells or between nerve cells and non-nerve cells. This process is termed ‘chemical neurotransmission’ and was first demonstrated, for nerves to the heart, by the German pharmacologist Loewi in 1921. Chemical transmission involving acetylcholine is known as ‘cholinergic’.

Acetylcholine acts as a transmitter between motor nerves and the fibres of skeletal muscle at all neuromuscular junctions. At this type of synapse, the nerve terminal is closely apposed to the cell membrane of a muscle fibre at the so-called motor end plate. On release, acetylcholine acts almost instantly, to cause a sequence of chemical and physical events (starting with depolarization of the motor endplate) which cause contraction of the muscle fibre. This is exactly what is required for voluntary muscles in which a rapid response to a command is required. The action of acetylcholine is terminated rapidly, in around 10 milliseconds; an enzyme (cholinesterase) breaks the transmitter down into choline and an acetate ion. The choline is then available for re-uptake into the nerve terminal.

These same principles apply to cholinergic transmission at sites other than neuromuscular junctions, although the structure of the synapses differs. In the autonomic nervous system these include nerve-to-nerve synapses at the relay stations (ganglia) in both the sympathetic and the parasympathetic divisions, and the endings of parasympathetic nerve fibres on non-voluntary (smooth) muscle, the heart, and glandular cells; in response to activation of this nerve supply, smooth muscle contracts (notably in the gut), the frequency of heart beat is slowed, and glands secrete. Acetylcholine is also an important transmitter at many sites in the brain at nerve-to-nerve synapses.

To understand how acetylcholine brings about a variety of effects in different cells it is necessary to understand membrane receptors. In post-synaptic membranes (those of the cells on which the nerve fibres terminate) there are many different sorts of receptors and some are receptors for acetylcholine. These are protein molecules that react specifically with acetylcholine in a reversible fashion. It is the complex of receptor combined with acetylcholine which brings about a biophysical reaction, resulting in the response from the receptive cell. Two major types of acetylcholine receptors exist in the membranes of cells. The type in skeletal muscle is known as ‘nicotinic’; in glands, smooth muscle, and the heart they are ‘muscarinic’; and there are some of each type in the brain. These terms are used because nicotine mimics the action of acetylcholine at nicotinic receptors, whereas muscarine, an alkaloid from the mushroom Amanita muscaria, mimics the action of acetylcholine at the muscarinic receptors.

— Alan W. Cuthbert

See also autonomic nervous system; neurotransmitters.

The acetyl derivative of choline, produced at cholinergic nerve endings both in the brain, where it acts as a chemical transmitter, and at the junctions between nerves and muscles, where it stimulates muscle contraction.

1. an acetate ester of choline that serves as a neurohumoral agent in the transmission of an impulse in autonomic ganglia, parasympathetic postganglionic fibers, and somatic motor fibers. n 2. an ester of choline actively involved as a chemical mediator at the neuromuscular junction, at autonomic ganglia, and between parasympathetic nerve endings and visceral effectors.

For more information on acetylcholine, visit Britannica.com.

A neurotransmitter synthesized from acetic acid and choline in the synaptic knobs of some nerve endings. It is released by all neurones that stimulate skeletal muscles, and neurones of the parasympathetic nervous system. ACh elicits action potentials in nerve and muscle cells by making them more permeable to sodium ions. Its effect is short-lived because it is destroyed by acetylcholinesterase. Acetylcholine was the first neurotransmitter to be identified.

Acetylcholine

The acetic acid ester of choline, normally present in many parts of the body and having important physiological functions. It is a neurotransmitter at cholinergic synapses in the central, sympathetic and parasympathetic nervous systems. It is not used clinically but it is the classical cholinergic agonist. Abbreviated ACh.

• a. receptors — structures located at the endorgans, e.g. at the skeletal muscle fibers. The myofibers are stimulated to contract by the interaction of acetylcholine with acetylcholine receptors which are located on the motor end plate or postsynaptic sarcolemma. See also neuromuscular junction.

Acetylcholine
Systematic (IUPAC) name
2-acetoxy-N,N,N-trimethylethanaminium
Identifiers
CAS number	51-84-3
ATC code	S01EB09
PubChem	187
DrugBank	EXPT00412
Chemical data
Formula	C7H16NO2
Mol. mass	146.21 g/mol
SMILES	search in eMolecules, PubChem
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	approximately 2 minutes
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status	legal with license
Routes	?

The chemical compound acetylcholine, often abbreviated as ACh, was the first neurotransmitter to be identified. It is a chemical transmitter 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 somatic nervous system (SNS). Acetylcholine is the neurotransmitter in all autonomic ganglia.

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.

Acetylcholine (ACh) was first identified in 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 name vagusstoff because it was released from the vagus nerve. Both received the 1936 Nobel Prize in Physiology or Medicine for their work.

Later work showed that when acetylcholine binds to acetylcholine receptors on skeletal muscle fibers, it opens ligand gated sodium channels in the membrane. Sodium ions then enter the muscle cell, stimulating muscle contraction. Acetylcholine, while inducing contraction of skeletal muscles, instead induces decreased contraction in cardiac muscle fibers. This distinction is attributed to differences in receptor structure between skeletal and cardiac fibers. Acetylcholine is also used in the brain, where it tends to cause excitatory actions. The glands that receive impulses from the parasympathetic part of the autonomic nervous system are also stimulated in the same way.

Synthesis and Degradation

Acetylcholine is synthesized in certain neurons by the enzyme choline acetyltransferase from the compounds choline and acetyl-CoA. Organic mercurial compounds have a high affinity for sulfhydryl groups, which causes dysfunction of the enzyme choline acetyl transferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function.

Normally, 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. The devastating effects of organophosphate-containing nerve agents (e.g. Sarin gas) are due to their irreversible inactivation of this enzyme. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands and central nervous system; victims commonly die of suffocation as they cannot relax their diaphragm. Other organophosphates and some carbamates are effective insecticides because they inhibit acetylcholinasterase in insects. On the other hand, since a shortage of acetylcholine in the brain has been associated with Alzheimer's disease, some drugs that inhibit acetylcholinesterase are used in the treatment of that disease. A recent study has shown that THC is one such drug, effective at reducing the formation of characteristic neurofibrillary tangles and amyloid beta plaques^[1].

Release sites

• Acetylcholine is released in the autonomic nervous system:
  • pre- and post-ganglionic parasympathetic neurons
  • preganglionic sympathetic neurons (and also postganglionic sudomotor neurons, i.e., the ones that control sweating)

Botulin acts by suppressing the release of acetylcholine; where the venom from a black widow spider has the reverse effect.

• all preganglionic autonomic fibers including:
  • all preganglionic sympathetic fibers
  • all preganglionic parasympathetic fibers
  • preganglionic sympathetic fibers to suprarenal medulla, the modified sympathetic ganglion. On stimulation by acetylcholine, it releases adrenaline and noradrenaline.
• all postganglionic parasympathetic fibers
• some postganglionic sympathetic fibers
  • secretory fibers to sweat glands
  • vasodilator fibers to blood vessels of skeletal muscles

Pharmacology

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 discover the receptors.

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 are on muscle end plates, autonomic ganglia (both sympathetic and parasympathetic), and in the CNS.^[2]

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, and its action on muscarinic AChRs that increased pupil size was 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.

The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces antibodies against acetylcholine receptors, and thus inhibits proper acetylcholine signal transmission. Over time the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine or physostigmine) 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.

Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Cholinesterase inhibitors, an example of enzyme inhibitors, 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). Clinically they are used to reverse the action of muscle relaxants, to treat myasthenia gravis and in Alzheimer's disease (rivastigmine, which increases cholinergic activity in the brain).

Neuromodulatory Effects

In the central nervous system, ACh has a variety of effects as a neuromodulator.

ACh is involved with synaptic plasticity. It 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.

Acetylcholine also has other effects on excitability of neurons. Its presence causes a slow depolarization by blocking a tonically active K⁺ current, which increases neuronal excitability. Paradoxically, it increases spiking activity in inhibitory interneurons while decreasing strength of synaptic transmission from those cells. This decrease in synaptic transmission also occurs selectively at some excitatory cells: for instance, it has an effect on intrinsic and associational fibers in layer Ib of piriform cortex, but has no effect on afferent fibers in layer Ia. Similar laminar selectivity has been shown in dentate gyrus and region CA1 of the hippocampus. One theory to explain this paradox interprets acetylcholine neuromodulation in the neocortex as modulating the estimate of expected uncertainty, acting counter to norepinephrine (NE) signals for unexpected uncertainty. Both 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.

Drugs Acting on the ACh System

ACh Receptor Agonists

Direct Acting

• Acetylcholine
• Bethanechol
• Carbachol
• Cevimeline
• Pilocarpine
• Suberylcholine
• Nicotine (in small doses)

Indirect Acting (reversible)

Reversibly inhibit the enzyme acetylcholinesterase (which breaks down acetylcholine), thereby increasing acetylcholine levels.

• Ambenomium
• Donepezil
• Edrophonium
• Galantamine
• Neostigmine
• Physostigmine
• Pyridostigmine
• Rivastigmine
• Tacrine
• Carbamate Insecticides (Aldicarb)

Indirect Acting (irreversible)

Semi-permanently inhibit the enzyme acetylcholinesterase.

• Echothiophate
• Isoflurophate
• Organophosphate Insecticides (Malathion, Parathion, Azinphos Methyl, Chlorpyrifos, among others)

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

Other / Uncategorized / Unknown

• surugatoxin

References

1. ^ Eubanks LM, Rogers CJ, Beuscher AE 4th, Koob GF, Olson AJ, Dickerson TJ, Janda KD. "A molecular link between the active component of marijuana and Alzheimer's disease pathology." Molecular Pharmaceutics. 2006 Nov-Dec; 3(6):773-7. PMID 17140265
2. ^ Katzung, B.G. (2003). Basic and Clinical Pharmacology (9th ed.). McGraw-Hill Medical. ISBN 0-07-141092-9

• Brenner, G. M. and Stevens, C. W. (2006). Pharmacology (2nd ed.). Philadelphia, PA: W.B. Saunders Company (Elsevier). ISBN 1-4160-2984-2
• Canadian Pharmacists Association (2000). Compendium of Pharmaceuticals and Specialties (25th ed.). Toronto, ON: Webcom. ISBN 0-919115-76-4
• Carlson, NR (2001). Physiology of Behavior (7th ed.). Needham Heights, MA: Allyn and Bacon. ISBN 0-205-30840-6
• Gershon, Michael D. (1998). The Second Brain. New York, NY: HarperCollins. ISBN 0-06-018252-0
• Hasselmo, ME. "Neuromodulation and cortical function: Modeling the physiological basis of behavior." Behavioral Brain Research. 1995 Feb; 67(1):1-27. PMID 7748496
• Yu, AJ & Dayan, P. "Uncertainty, neuromodulation, and attention." Neuron. 2005 May 19; 46(4):681-92. PMID 15944135

External links

• Washington University (St. Louis) writeup

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)

Dansk (Danish)
n. - acetylklorin

Nederlands (Dutch)
acetylcholine (bepaalde neurotransmitter)

Français (French)
n. - acétylcholine

Deutsch (German)
n. - (chem.) Acetylcholin

Ελληνική (Greek)
n. - ακετυλχολίνη

Italiano (Italian)
acetilcolina

Português (Portuguese)
n. - acetilcolina (f) (Quím.)

Русский (Russian)
ацетилхолин

Español (Spanish)
n. - compuesto que transmite impulsos de fibras nerviosas

Svenska (Swedish)
n. - acetylkolin

中文（简体） (Chinese (Simplified))
醋胆素

中文（繁體） (Chinese (Traditional))
n. - 醋膽素

한국어 (Korean)
n. - 아세틸 콜린

日本語 (Japanese)
n. - アセチルコリン

עברית (Hebrew)
n. - ‮אצטילכולין (תרופה)‬

If you are unable to view some languages clearly, click here.

To select your translation preferences click here.