|Molar mass||146.21 g mol−1|
|approximately 2 minutes|
(what is this?) |
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
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 (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 name Vagusstoff 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.
|Synthesizing enzyme||Choline acetyltransferase (ChAT)|
|Metabolizing enzyme||Acetylcholinesterase (AChE)|
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 excitatory actions.
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:
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 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 disease. ACh has also been shown to be the most important inducer of REM sleep.
There are three ACh pathways in the CNS.
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. In the basal forebrain, it originates from the basal optic nucleus of Meynert and medial septal nucleus:
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.
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.
Acetylcholine also has other effects on neurons. One effect is to cause a slow depolarization by blocking a tonically-active K+ current, which increases neuronal excitability. An effect upon postsynaptic M4-muscarinic ACh receptors is to open inward-rectifier potassium ion channel (Kir) and cause inhibition.
These two effects happen upon neurons in different neuron layers. For instance, the excitation effect acts 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.
In the cerebral cortex, ACh inhibits layer 4 medium spiny neurons, the main targets of thalamocortical inputs while exciting pyramidal cells 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.
Another theory 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'.
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.
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 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.
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 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.
Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it.
Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand. Agonists increase the level of receptor activation, antagonists reduce it.
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.
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).
The following substances reversibly inhibit the enzyme acetylcholinesterase (which breaks down acetylcholine), thereby increasing acetylcholine levels.
Semi-permanently inhibit the enzyme acetylcholinesterase.
Victims of organophosphate-containing nerve agents commonly die of suffocation as they cannot relax their diaphragm.