Acetylcholine

From Wikipedia, the free encyclopedia

Jump to navigationJump to search

Acetylcholine?(ACh) is an?organic chemical?that functions in the brain and body of many types of animals (including humans) as a?neurotransmitter—a chemical message released by nerve cells to send signals to other cells, such as neurons, muscle cells and gland cells.[1]?Its name is derived from its chemical structure: it is an?ester?of?acetic acid?and?choline. Parts in the body that use or are affected by acetylcholine are referred to as?cholinergic. Substances that increase or decrease the overall activity of the cholinergic system are called?cholinergics?and?anticholinergics, respectively.

Acetylcholine is the neurotransmitter used at the?neuromuscular junction—in other words, it is the chemical that?motor neurons?of the nervous system release in order to activate muscles. This property means that Drugs that affect cholinergic systems can have very dangerous effects ranging from paralysis to convulsions. Acetylcholine is also a neurotransmitter in the?autonomic nervous system, both as an internal transmitter for the?sympathetic nervous system?and as the final product released by the?parasympathetic nervous system.[1]?Acetylcholine is the primary neurotransmitter of the parasympathetic nervous system.[2]

In the brain, acetylcholine functions as a?neurotransmitter?and as a?neuromodulator. The brain contains a number of cholinergic areas, each with distinct functions; such as playing an important role in arousal, attention, memory and motivation.[3]

Acetylcholine has also been traced in cells of non-neural origins and microbes. Recently, enzymes related to its synthesis, degradation and cellular uptake have been traced back to early origins of unicellular eukaryotes.[4]?The protist pathogen?Acanthamoeba?spp. has shown the presence of ACh, which provides growth and proliferative signals via a membrane located M1-muscarinic receptor homolog.[5]

Partly because of its muscle-activating function, but also because of its functions in the autonomic nervous system and brain, many important Drugs exert their effects by altering cholinergic transmission. Numerous venoms and toxins produced by plants, animals, and bacteria, as well as chemical?nerve agents?such as?Sarin, cause harm by inactivating or hyperactivating muscles through their influences on the neuromuscular junction. Drugs that act on?muscarinic acetylcholine receptors, such as?atropine, can be poisonous in large quantities, but in smaller doses they are commonly used to treat certain heart conditions and eye problems.?Scopolamine, which acts mainly on muscarinic receptors in the brain, can cause?delirium,?hallucinations, and?amnesia. The addictive qualities of?nicotine?are derived from its effects on?nicotinic acetylcholine receptors?in the brain.

Contents

·?1Chemistry

·?2Biochemistry

·?3Functions

·?3.1Cellular effects

·?3.2Neuromuscular junction

·?3.3Autonomic nervous system

·?3.4Central nervous system

·?4Diseases and disorders

·?4.1Myasthenia gravis

·?5Pharmacology

·?5.1Nicotinic receptors

·?5.2Muscarinic receptors

·?5.3Cholinesterase inhibitors

·?5.4Synthesis inhibitors

·?5.5Release inhibitors

·?6Comparative biology and evolution

·?7History

·?8See also

·?9Specific references

·?10General bibliography

·?11External links

Chemistry[edit]

Acetylcholine is a?choline?molecule that has been?acetylated?at the?oxygen?atom. Because of the presence of a highly polar, charged?ammonium?group, acetylcholine does not penetrate lipid membranes. Because of this, when the molecule is introduced externally, it remains in the extracellular space and does not pass through the blood–brain barrier.

Biochemistry[edit]

Acetylcholine is synthesized in certain?neurons?by the?enzyme?choline acetyltransferase?from the compounds?choline?and?acetyl-CoA. Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area is the nucleus basalis of Meynert in the basal forebrain.[6][7]?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, causing paralysis of the muscles needed for breathing and stopping the beating of the heart.

Functions[edit]

?

Acetylcholine pathway.

Acetylcholine functions in both the?central nervous system?(CNS) and the?peripheral nervous system?(PNS). In the CNS, cholinergic projections from the?basal forebrain?to the?cerebral cortex?and?hippocampus?support the?cognitive?functions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system.

Cellular effects[edit]

Main article:?Acetylcholine receptor

?

Acetylcholine processing in a synapse. After release acetylcholine is broken down by the enzyme?acetylcholinesterase.

Like many other biologically active substances, acetylcholine exerts its effects by binding to and activating?receptors?located on the surface of cells. There are two main classes of acetylcholine receptor,?nicotinic?and?muscarinic.?They are named for chemicals that can selectively activate each type of receptor without activating the other:?muscarine?is a compound found in the mushroom?Amanita muscaria(毒蠅鵝膏菌，拉丁學(xué)名：[Amanita miscaria (L.: Fr.) Pers. ex Hook.毒蠅傘]，又稱哈蟆菌、捕蠅菌、毒蠅菌、毒蠅傘。為人所知的，是對于吃進(jìn)去后的影響有不可預(yù)測性。根據(jù)棲息地和每種體重的大量攝取結(jié)果，癥狀可以是有變化的，從惡心、痙攣，到倦睡、膽堿激素危機(jī)類癥狀（低血壓、流汗與唾液過多分泌）、視覺和聽覺的扭曲、情緒改變、興奮、弛緩、協(xié)調(diào)失能和眩暈都有。有些案例當(dāng)中，嚴(yán)重毒性還會導(dǎo)致妄想。);?nicotine?is found in tobacco.

Nicotinic acetylcholine receptors?are?ligand-gated ion channels?permeable to?sodium,?potassium, and?calcium?ions.

(從視頻紀(jì)錄片獲得資料，VTA多巴胺能神經(jīng)細(xì)胞上的acetylcholine receptors就是Nicotinic acetylcholine receptors，在該視頻中，還認(rèn)為吸煙成癮的原因是Nicotine順著血液流到VTA導(dǎo)致的。那么，這樣一來，就意味著Nicotinic acetylcholine receptors是離子型通道，而不是G-protein coupled receptor，那么pontine acetylcholine system對basal ganglia及多巴胺系統(tǒng)的影響就應(yīng)該是即時效果，而不應(yīng)該導(dǎo)致代謝率的長期升高，對應(yīng)著“喜歡”的感覺。)?

In other words, they are ion channels embedded in cell membranes, capable of switching from a closed to an open state when acetylcholine binds to them; in the open state they allow ions to pass through. Nicotinic receptors come in two main types, known as muscle-type and neuronal-type. The muscle-type can be selectively blocked by?curare, the neuronal-type by?hexamethonium. The main location of muscle-type receptors is on muscle cells, as described in more detail below. Neuronal-type receptors are located in autonomic ganglia (both sympathetic and parasympathetic), and in the central nervous system.

Muscarinic acetylcholine receptors?have a more complex mechanism, and affect target cells over a longer time frame. In mammals, five subtypes of muscarinic receptors have been identified, labeled M1 through M5.All of them function as?G protein-coupled receptors, meaning that they exert their effects via a?second messenger system.?The M1, M3, and M5 subtypes are?Gq-coupled; they increase intracellular levels of?IP3and?calcium?by activating?phospholipase C. Their effect on target cells is usually excitatory. The M2 and M4 subtypes are?Gi/Go-coupled; they decrease intracellular levels of?cAMP?by inhibiting?adenylate cyclase. Their effect on target cells is usually inhibitory.

（acetylcholine在大腦皮層的抑制作用應(yīng)該不是立馬產(chǎn)生，而是要過一會才發(fā)揮作用，但是對大腦皮層中的興奮作用是即時的，那么，在微放大環(huán)路的信息強(qiáng)化作用下，很短時間內(nèi)重復(fù)的外界信息刺激發(fā)生時，正好趕上后返勁兒遲來的抑制效果，而這個重復(fù)的外界信息刺激最容易激發(fā)被微放大環(huán)路強(qiáng)化的信息，即之前瞬間形成的終生記憶，所謂印象最深刻的記憶，注意這里的記憶都是針對新鮮的外來信息，即形成新的記憶。關(guān)鍵點(diǎn)是G protein-coupled receptors的效果是要過一段時間才能顯現(xiàn)，而acetylcholine的作用時間又極短，從而在大腦皮層形成特有的new information永久記憶形成模式。老年癡呆癥的最最初癥狀應(yīng)該是對新鮮外界信息的記憶能力喪失，即不能形成瞬時的印象最深刻記憶的感覺，然后因?yàn)殚L期缺失acetylcholine，不能夠去抑制那些不需要的神經(jīng)細(xì)胞，導(dǎo)致這些神經(jīng)細(xì)胞也跟著變得敏感起來，增加消耗量，增加負(fù)擔(dān)，同時最重要的是抹平了原有的記憶神經(jīng)細(xì)胞獨(dú)有的敏感性，變得不突出，變相抹平了記憶。初期來說，大量原本休眠或不那么敏感的神經(jīng)細(xì)胞變得敏感，消耗量增加，這也是變相增加皮層的負(fù)擔(dān)，因?yàn)檠髁康脑黾硬粫艽?，對于海馬皮層來說就會增加平均輸出量，從而增加NE濃度（我覺得海馬皮層的基礎(chǔ)活動會增加NE濃度），NE濃度的增加表現(xiàn)為DA系統(tǒng)一定程度的被抑制，副交感系統(tǒng)也被抑制較多（這個會導(dǎo)致serotonin減少），外在表現(xiàn)為脾氣暴躁，易怒，然后再進(jìn)一步，在少serotonin、多cortisol情況下，海馬皮層的神經(jīng)細(xì)胞減少，萎縮，從而降低了NE濃度，DA系統(tǒng)能夠很多地活動，副交感系統(tǒng)活動增加，serotonin濃度也恢復(fù)并增加，外在表現(xiàn)為后期的傻樂狀態(tài)。acetylcholine對大腦皮層的抑制效果原來是有很大的保護(hù)作用，減少皮層的消耗負(fù)擔(dān)，既是保護(hù)，也是記憶新鮮事物。

應(yīng)該說acetylcholine對海馬體的影響還是很大。而海馬體的體積變化會很明顯地反映在行為上。）?

Muscarinic acetylcholine receptors are found in both the central nervous system and the peripheral nervous system of the heart, lungs, upper gastrointestinal tract, and sweat glands.

Neuromuscular junction[edit]

?

Muscles contract when they receive signals from motor neurons. The neuromuscular junction is the site of the signal exchange. The steps of this process in vertebrates occur as follows: (1) The action potential reaches the axon terminal. (2) Calcium ions flow into the axon terminal. (3) Acetylcholine is released into the?synaptic cleft. (4) Acetylcholine binds to postsynaptic receptors. (5) This binding causes ion channels to open and allows sodium ions to flow into the muscle cell. (6) The flow of sodium ions across the membrane into the muscle cell generates an action potential which induces muscle contraction. Labels: A: Motor neuron axon B: Axon terminal C: Synaptic cleft D: Muscle cell E: Part of a Myofibril

Main article:?Neuromuscular junction

Acetylcholine is the substance the nervous system uses to activate?skeletal muscles, a kind of striated muscle. These are the muscles used for all types of voluntary movement, in contrast to?smooth muscle tissue, which is involved in a range of involuntary activities such as movement of food through the gastrointestinal tract and constriction of blood vessels. Skeletal muscles are directly controlled by?motor neurons?located in the?spinal cord?or, in a few cases, the?brainstem. These motor neurons send their axons through?motor nerves, from which they emerge to connect to muscle fibers at a special type of?synapse?called the?neuromuscular junction.

When a motor neuron generates an?action potential, it travels rapidly along the nerve until it reaches the neuromuscular junction, where it initiates an electrochemical process that causes acetylcholine to be released into the space between the presynaptic terminal and the muscle fiber. The acetylcholine molecules then bind to nicotinic ion-channel receptors on the muscle cell membrane, causing the ion channels to open. Sodium ions then flow into the muscle cell, initiating a sequence of steps that finally produce?muscle contraction.

Factors that decrease release of acetylcholine (and thereby affecting?P-type calcium channels):[8]

1.?Antibiotics?(clindamycin,?polymyxin)

2.?Magnesium:?antagonizes P-type calcium channels

3.?Hypocalcemia

4.?Anticonvulsants

5.?Diuretics?(furosemide)

6.?Eaton-Lambert syndrome: inhibits P-type calcium channels

7.?Myasthenia gravis

8.?Botulinum toxin: inhibits SNARE proteins

Calcium channel blockers?(nifedipine, diltiazem) do not affect P-channels. These Drugs affect?L-type calcium channels.

Autonomic nervous system[edit]

?

Components and connections of the?parasympathetic nervous system.

The?autonomic nervous system?controls a wide range of involuntary and unconscious body functions. Its main branches are the?sympathetic nervous system?and?parasympathetic nervous system. Broadly speaking, the function of the sympathetic nervous system is to mobilize the body for action; the phrase often invoked to describe it is?fight-or-flight. The function of the parasympathetic nervous system is to put the body in a state conducive to rest, regeneration, digestion, and reproduction; the phrase often invoked to describe it is "rest and digest" or "feed and breed". Both of these aforementioned systems use acetylcholine, but in different ways.

At a schematic level, the sympathetic and parasympathetic nervous systems are both organized in essentially the same way: preganglionic neurons in the central nervous system send projections to neurons located in autonomic ganglia, which send output projections to virtually every tissue of the body. In both branches the internal connections, the projections from the central nervous system to the autonomic ganglia, use acetylcholine as a neurotransmitter to innervate (or excite) ganglia neurons. In the parasympathetic nervous system the output connections, the projections from ganglion neurons to tissues that don't belong to the nervous system, also release acetylcholine but act on muscarinic receptors. In the sympathetic nervous system the output connections mainly release?noradrenaline, although acetylcholine is released at a few points, such as the?sudomotor?innervation of the sweat glands.

Direct vascular effects[edit]

Acetylcholine in the?serum?exerts a direct effect on?vascular tone?by binding to?muscarinic receptors?present on vascular?endothelium. These cells respond by increasing production of?nitric oxide, which signals the surrounding smooth muscle to relax, leading to?vasodilation.[9]

Central nervous system[edit]

?

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 on plasticity, arousal and?reward. ACh has an important role in the enhancement of alertness when we wake up,[10]?in sustaining attention?[11]?and in learning and memory.[12]

Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be associated with the memory deficits associated with?Alzheimer's disease.[13]?ACh has also been shown to promote?REM?sleep.[14]

In the brainstem acetylcholine originates from the?Pedunculopontine nucleus?and?laterodorsal tegmental nucleus?collectively known as the mesopontine tegmentum?area or pontomesencephalotegmental complex.[15][16]?In the basal forebrain, it originates from the?basal nucleus of Meynert?and medial?septal nucleus:

·?The?pontomesencephalotegmental complex?acts mainly on?M1 receptors?in the?brainstem, deep?cerebellar nuclei,?pontine nuclei,?locus coeruleus,?raphe nucleus,?lateral reticular nucleus?and?inferior olive.[16]?It also projects to the?thalamus,?tectum,?basal ganglia?and?basal forebrain.[15]

（這里也與其他資料相矛盾，首先沒有提到VTA，其次視頻資料中明確指出在VTA處的受體是nicotinic。在這么關(guān)鍵的結(jié)構(gòu)上，居然存在這么多不清楚、相矛盾的地方。）

·?Basal nucleus of Meynert?acts mainly on?M1 receptors?in the?neocortex

（這里與其他詞條相矛盾，在nucleus basalis詞條中明確指出在第一二層中起到抑制作用，而M1起到的是興奮作用。在這么關(guān)鍵的結(jié)構(gòu)上，居然存在這么多不清楚、相矛盾的地方。）.

·?Medial?septal nucleus?acts mainly on?M1 receptors?in the?hippocampus?and parts of the?cerebral cortex.（Medial?septal nucleus與diagonal band of broca都能在海馬皮層產(chǎn)生θ腦電波，根據(jù)其波形特點(diǎn)，似乎這與M1 receptors的興奮作用有些關(guān)系。）

In addition, ACh acts as an important internal transmitter in the?striatum, which is part of the?basal ganglia. It is released by cholinergic?interneurons. In humans, non-human primates and rodents, these interneurons respond to salient environmental stimuli with responses that are temporally aligned with the responses of dopaminergic neurons of the?substantia nigra.[17][18]

Memory[edit]

Acetylcholine has been implicated in?learning?and?memory?in several ways. The anticholinergic Drug,?scopolamine, impairs acquisition of new information in humans[19]?and animals.[12]?In animals, disruption of the supply of acetylcholine to the?neocortex?impairs the learning of simple discrimination tasks, comparable to the acquisition of factual information[20]?and disruption of the supply of acetylcholine to the?hippocampus?and adjacent cortical areas produces forgetfulness, comparable to?anterograde amnesia?in humans.[21]

Diseases and disorders[edit]

Myasthenia gravis[edit]

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 the symptoms of this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the synaptic cleft (the space between nerve and muscle).

Pharmacology[edit]

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.

Acetylcholine itself does not have therapeutic value?as a Drug for intravenous administration because of?its multi-faceted action (non-selective) and rapid inactivation by cholinesterase. However, it is used in the form of eye drops to cause constriction of the pupil during cataract surgery, which facilitates quick post-operational recovery.

Nicotinic receptors[edit]

Main article:?Nicotinic receptor

Nicotine binds to and activates?nicotinic acetylcholine receptors, mimicking the effect of acetylcholine at these receptors. ACh opens a?Na+?channel?upon binding so that Na+?flows into the cell. This causes a depolarization, and results in an excitatory post-synaptic potential. Thus, ACh is excitatory on skeletal muscle; the electrical response is fast and short-lived.?Curares?are arrow poisons, which act at nicotinic receptors and have been used to develop clinically useful therapies.

Muscarinic receptors[edit]

Main article:?Muscarinic receptor

Muscarinic receptors form?G protein-coupled receptor?complexes in the?cell membranes?of?neurons?and other cells.?Atropine?is a non-selective competitive antagonist with Acetylcholine at muscarinic receptors.

Cholinesterase inhibitors[edit]

Main article:?Cholinesterase inhibitors

Many ACh receptor agonists work indirectly by inhibiting the enzyme?acetylcholinesterase. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system, which can result in fatal convulsions if the dose is high.

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). Many toxins and venoms produced by plants and animals also contain cholinesterase inhibitors. In clinical use, they are administered in low doses 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).

Synthesis inhibitors[edit]

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[edit]

Botulinum toxin?(Botox) acts by suppressing the release of acetylcholine, whereas the venom from a?black widow spider?(alpha-latrotoxin) has the reverse effect. ACh inhibition causes?paralysis. When bitten by a?black widow spider, one experiences the wastage of ACh supplies and the muscles begin to contract. If and when the supply is depleted,?paralysis?occurs.

Comparative biology and evolution[edit]

Acetylcholine is used by organisms in all domains of life for a variety of purposes. It is believed that choline, a precursor to acetylcholine, was used by single celled organisms billions of years ago[citation needed]?for synthesizing cell membrane phospholipids.[22]?Following the evolution of choline transporters, the abundance of intracellular choline paved the way for choline to become incorporated into other synthetic pathways, including acetylcholine production. Acetylcholine is used by bacteria, fungi, and a variety of other animals. Many of the uses of acetylcholine rely on its action on ion channels via GPCRs like membrane proteins.

The two major types of acetylcholine receptors, muscarinic and nicotinic receptors, have convergently evolved to be responsive to acetylcholine. This means that rather than having evolved from a common homolog, these receptors evolved from separate receptor families. It is estimated that the nicotinic receptor family dates back longer than 2.5 billion years.[22]?Likewise, muscarinic receptors are thought to have diverged from other GPCRs at least 0.5 billion years ago. Both of these receptor groups have evolved numerous subtypes with unique ligand affinities and signaling mechanisms. The diversity of the receptor types enables acetylcholine to create varying responses depending on which receptor types are activated, and allow for acetylcholine to dynamically regulate physiological processes. ACh receptors are related to?5-HT3?(serotonin),?GABA, and?Glycine receptors, both in sequence and structure, strongly suggesting that they have a common evolutionary origin.[23]

History[edit]

In 1867,?Adolf von Baeyer?resolved the structures of?choline?and acetylcholine and synthetized them both, referring to the latter as "acetylneurin" in the study.[24][25]?Choline is a precursor for acetylcholine. This is why?Frederick Walker Mott?and?William Dobinson Halliburton?noted in 1899 that choline injections decreased the blood pressure of animals.[26][25]?Acetylcholine was first noted to be biologically active in 1906, when?Reid Hunt?(1870–1948) and?René de M. Taveau?found that it decreased?blood pressure?in exceptionally tiny doses.[27][25][28]

In 1914,?Arthur J. Ewins?was the first to extract acetylcholine from nature. He identified it as the blood pressure decreasing contaminant from some?Claviceps purpurea?ergot?extracts, by the request of?Henry Hallett Dale.[25]?Later in 1914, Dale outlined the effects of acetylcholine at various types of peripheral synapses and also noted that it lowered the blood pressure of cats via?subcutaneous injections?even at doses of one?nanogram.[29][25]

The concept?neurotransmitters?was unknown before 1921, when?Otto Loewi?noted that the?vagus nerve?secreted a substance that inhibited the?heart muscle?whilst working as a professor in the?University of Graz. He named it?vagusstoff?("vagus substance"), noted it to be a?structural analog?of choline and suspected it to be acetylcholine.[30][31]?In 1926, Loewi and E. Navratil deduced that the compound is probably acetylcholine, as vagusstoff and synthetic acetylcholine lost their activity in a similar manner when in contact with tissue?lysates?that contained acetylcholine-degrading enzymes (now known to be?cholinesterases).[32][33]?This conclusion was accepted widely. Later studies confirmed the function of acetylcholine as a neurotransmitter.[31]

In 1936, H. H. Dale and O. Loewi shared the?Nobel Prize in Physiology or Medicine?for their studies of acetylcholine and nerve impulses.[25]

?