acetylcholine: Definition and Much More from Answers.com

acetylcholine


Acetylcholine
Systematic (IUPAC) name
2-acetoxy-N,N,N-trimethylethanaminium
Identifiers
CAS number51-84-3
ATC codeS01EB09
PubChem187
DrugBankEXPT00412
Chemical data
FormulaC7H16NO2
Mol. mass 146.21 g/mol
SMILES search ineMolecules,PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life approximately 2 minutes
Excretion  ?
Therapeutic considerations
Pregnancy cat.
?
Legal status
Routes  ?
Thechemical compound acetylcholine, often abbreviated as ACh, wasthe firstneurotransmitter to be identified. It is a chemical transmitter in both theperipheral nervous system (PNS) andcentral nervous system (CNS) in many organisms includinghumans.Acetylcholine is the neurotransmitter in allautonomic ganglia. In layman‘s terms, itis a chemical that allows neurons to communicate with each other within humans and other organisms.
Chemistry
Acetylcholine is anester ofacetic acid andcholine withchemical formulaCH3COOCH2CH2N+(CH3)3. This structure is reflected in the systematicname, 2-acetoxy-N,N,N-trimethylethanaminium.
Acetylcholine (ACh) was first identified in 1914 byHenry Hallett Dale for itsactions on heart tissue. It was confirmed as a neurotransmitter byOtto Loewi who initiallygave it the namevagusstoff because it was released from thevagus nerve. Both received the 1936Nobel Prize inPhysiology or Medicine for their work.
Later work showed that when acetylcholine binds toacetylcholine receptors onskeletal muscle fibers, it opens ligand gated sodium channels in the membrane. Sodiumions then enter the muscle cell, stimulating muscle contraction. Acetylcholine, while inducing contraction of skeletal muscles,instead induces decreased contraction incardiac muscle fibers. This distinction isattributed to differences in receptor structure between skeletal and cardiac fibers. Acetylcholine is also used in thebrain, where it tends to cause excitatory actions. Theglands thatreceive impulses from the parasympathetic part of theautonomic nervous systemare also stimulated in the same way.
Synthesis and Degradation
Acetylcholine is synthesized in certainneurons by theenzymecholine acetyltransferase from the compoundscholine andacetyl-CoA. Organic mercurial compounds have a high affinity forsulfhydryl groups, which causes dysfunction of the enzyme choline acetyl transferase. Thisinhibition may lead to acetylcholine deficiency, and can have consequences on motor function.
Normally, the enzymeacetylcholinesterase converts acetylcholine into theinactivemetabolitescholine andacetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine fromthe synapse is essential for proper muscle function. The devastating effects oforganophosphate-containing nerve agents (e.g.Sarin gas) are due to theirirreversible inactivation of this enzyme. The resulting accumulation of acetylcholine causes continuous stimulation of themuscles, glands and central nervous system; victims commonly die of suffocation as they cannot contract theirdiaphragm. Other organophosphates and somecarbamatesareeffective insecticides because they inhibit acetylcholinasterase ininsects. On the other hand, since a shortage of acetylcholinein thebrain has been associated withAlzheimer‘sdisease, some drugs that inhibit acetylcholinesterase are used in the treatment of that disease. A recent study[1] has shown thatTHC is one such drug, effective at reducing the formation of characteristicneurofibrillary tangles andamyloid beta plaques.
Release sites
Acetylcholine is released in theautonomic nervous system: pre- and post-ganglionicparasympathetic neurons
preganglionicsympathetic neurons (and also postganglionic sudomotor neurons, i.e., the ones that controlsweating)
Botulin acts by suppressing the release of acetylcholine; where the venom from ablack 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 releasesadrenaline andnoradrenaline.
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),nicotinicacetylcholine receptors (nAChR) andmuscarinic acetylcholinereceptors (mAChR). They are named for theligands used to discover the receptors.
Nicotinic AChRs areionotropic receptors permeable tosodium,potassium, andchloride ions. Theyare stimulated bynicotine and acetylcholine and blocked bycurare. Most peripheral AChRs are nicotinic, such as those on the heart and blood vessels or at theneuromuscular junction. They are also found in wide distribution through thebrain, but in relatively low numbers.
Muscarinic receptors aremetabotropic and affect neurons over a longer timeframe. They are stimulated bymuscarine and acetylcholine, and blocked byatropine. 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 included this compound, and its action on muscarinicAChRs that increased pupil size was used for attractiveness in many European cultures in the past. Now, ACh is sometimes usedduringcataract surgery to produce rapid constriction of the pupil. It must be administeredintraocularly becausecornealcholinesterasemetabolizes 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 inducemydriasis (dilation of the pupil) incardiopulmonary resuscitation and many other situations.
The diseasemyasthenia gravis, characterized by muscle weakness and fatigue, occurswhen the body inappropriately producesantibodiesagainst acetylcholine receptors, and thusinhibits proper acetylcholine signal transmission. Over time the motorend plate is destroyed. Drugs that competitively inhibitacetylcholinesterase (e.g., neostigmine or physostigmine) are effectivein treating this disorder. They allow endogenouslyreleased acetylcholine more time to interact with its respectivereceptor before being inactivated by acetylcholinesterase in thegap junction.
Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine.Cholinesterase inhibitors, an example ofenzymeinhibitors, increase the action of acetylcholine by delaying its degradation; some have been used asnerve agents (Sarin andVX nervegas) orpesticides (organophosphates and thecarbamates). Clinically they are used to reverse the action ofmuscle relaxants, to treatmyasthenia gravis and inAlzheimer‘s disease (rivastigmine, whichincreases cholinergic activity in the brain).
ACh Receptor Agonists
Direct Acting
Acetylcholine
Bethanechol
Carbachol
Cevimeline
Pilocarpine
Suberylcholine
Indirect Acting (reversible)
Reversibly inhibit the enzymeacetylcholinesterase (which breaks downacetylcholine), thereby increasing acetylcholine levels.
Ambenomium
Donepezil
Edrophonium
Galantamine
Neostigmine
Physostigmine
Pyridostigmine
Rivastigmine
Tacrine
CarbamateInsecticides (Aldicarb)
Indirect Acting (irreversible)
Semi-permanently inhibit the enzyme acetylcholinesterase.
Echothiophate
Isoflurophate
OrganophosphateInsecticides (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
Tubovurarine
Vecuronium
Others? / Uncategorized / Unknown
surugatoxin
Organophosphates block the breakdown of acetylcholine. Tetrachlorvinphos and other organophosphates operate by blocking acetylcholinesterase, which is an enzyme that breaks down acetylcholine.
Neuromodulatory Effects
In the central nervous system, ACh has a variety of effects as aneuromodulator.
Given its prominent role in learning, ACh is naturally involved withsynapticplasticity. It has been shown to enhance the amplitude of synaptic potentials followinglong-term potentiation in many regions, including thedentategyrus,CA1,piriform cortex, andneocortex. This effect most likely occurs either through enhancing currents throughNMDA receptors or indirectly by suppressingadaptation.The suppression of adaptation has been shown in brain slices of regions CA1,cingulatecortex, and piriform cortex as well asin vivo in catsomatosensory andmotor cortex by decreasing the conductance ofvoltage-dependent M currents andCa2+-dependentK+ currents.
Acetylcholine also has other effects on excitability of neurons. Its presence causes a slowdepolarization by blocking a tonically active K+ current, which increases neuronalexcitability. Paradoxically, it increases spiking activity in inhibitory interneurons whiledecreasing strength of synaptic transmission from those cells. This decrease in synaptic transmission also occurs selectively atsome excitatory cells: for instance, it has an effect on intrinsic and associational fibers in layer Ib of piriform cortex, buthas no effect on afferent fibers in layer Ia. Similar laminar selectivity has been shown in dentate gyrus and region CA1 of thehippocampus. One theory to explain this paradox interprets Acetylcholine neuromodulation in the neocortex as modulating theestimate of expected uncertainty, acting counter toNorepinephrine (NE) signals forunexpected uncertainty. Both would then decrease synaptic transition strength, but ACh would then be needed to counter theeffects of NE in learning a signal understood to be noisy.