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.
In the PNS, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system.
In the CNS, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system, which tends to cause excitatory actions.
In PNS
In the PNS, 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, 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.
preganglionic sympathetic fibers to suprarenal medulla, the modified sympathetic ganglion; on stimulation by acetylcholine, the suprarenal medulla releases adrenaline and noradrenaline
some postganglionic sympathetic fibers
sudomotor neurons to sweat glands.
In CNS
In the central nervous system, ACh has a variety of effects as a neuromodulator, e.g., for plasticity and excitability. Other effects are arousal and reward.
Structure
Acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system. It originates mainly in pontomesencephalotegmental complex, basal optic nucleus of Meynert and medial septal nucleus, and projects axons to vast areas of the brain:
The pontomesencephalotegmental complex acts mainly on M1 receptors in the brainstem .
Basal optic nucleus of Meynert acts mainly on M1 receptors in the neocortex.
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.
Excitability
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. It appears to be a paradox, however, that ACh 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'.
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 metabolitescholine 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.
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.[1]
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, 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 cornealcholinesterase 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 ACh 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
Acetylcholine receptor agonists 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.
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.
Alzheimer's disease
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[2].
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.
The following substances reversibly inhibit the enzyme acetylcholinesterase (which breaks down acetylcholine), thereby increasing acetylcholine levels.
Organic mercurial compounds 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 has the reverse effect.
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