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 [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 interfere with acetylcholine activity are called anticholinergics. 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]

The Acetylcholine (ACh), 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.[2] 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.[3] 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.

Partly because of its muscle-activating function, but also because of its functions in the autonomic nervous system and brain, a large number of 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 via 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 and amnesia. The addictive qualities of nicotine are derived from its effects on nicotinic acetylcholine receptors in the brain.

Clinical data
Physiological data
Source tissuesmotor neurons, parasympathetic nervous system, brain
Target tissuesskeletal muscles, brain, many other organs
Receptorsnicotinic, muscarinic
Agonistsnicotine, muscarine, cholinesterase inhibitors
Antagoniststubocurarine, atropine
Precursorcholine, acetyl-CoA
Biosynthesischoline acetyltransferase
CAS Number
PubChem CID


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 drug is introduced externally, it remains in the extracellular space and does not pass through the blood–brain barrier. A synonym of this drug is miochol.


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.[4][5] 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.


Acetylcholine Pathway
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

Cholinergic synapse
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; nicotine is found in tobacco.

Nicotinic acetylcholine receptors are ligand-gated ion channels permeable to sodium, potassium, and calcium ions. 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 IP3 and 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. 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

The Muscle Contraction Process
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

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):[6]

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) 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

1503 Connections of the Parasympathetic Nervous System
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) cholinergic neurons (neurons expressing nicotinic acetylcholine receptors). 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

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.[7]

Central nervous system

Nucleus basalis of Meynert - intermed mag
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,[8] in sustaining attention [9] and in learning and memory.[10]

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.[11] ACh has also been shown to promote REM sleep.[12]

In the brainstem acetylcholine originates from the Pedunculopontine nucleus and laterodorsal tegmental nucleus collectively known as the mesopontine tegmentum area or pontomesencephalotegmental complex.[13][14] In the basal forebrain, it originates from the basal 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 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.[15][16]


Acetylcholine has been implicated in learning and memory in several ways. The anticholinergic drug, scopolamine, impairs acquisition of new information in humans[17] and animals.[10] 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[18] and disruption of the supply of acetylcholine to the hippocampus and adjacent cortical areas produces forgetting comparable to anterograde amnesia in humans.[19]

Diseases and disorders

Myasthenia gravis

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 synaptic cleft (the space between nerve and muscle).


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.


Nicotine binds to and activates nicotinic acetylcholine receptors, mimicking the effect of acetylcholine at these receptors. When ACh interacts with a nicotinic ACh receptor, it opens a Na+ channel and Na+ ions flow into the membrane. 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.


Atropine is a non-selective competitive antagonist with Acetylcholine at muscarinic receptors.

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

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

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

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[2] for synthesizing cell membrane phospholipids.[20] 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[3].

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.[20] 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 creating varying responses depending on which receptor types are activated, and allow for acetylcholine to dynamically regulate physiological processes.


Acetylcholine (ACh) was first identified in 1915 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.


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External links

Acetylcholine receptor

An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.


Acetylcholinesterase (HGNC symbol ACHE; EC, also known as AChE or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme that catalyzes the breakdown of acetylcholine and of some other choline esters that function as neurotransmitters. AChE is found at mainly neuromuscular junctions and in chemical synapses of the cholinergic type, where its activity serves to terminate synaptic transmission. It belongs to carboxylesterase family of enzymes. It is the primary target of inhibition by organophosphorus compounds such as nerve agents and pesticides.

Acetylcholinesterase inhibitor

An acetylcholinesterase inhibitor (often abbreviated AChEI) or anti-cholinesterase is a chemical or a drug that inhibits the acetylcholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine. Acetylcholinesterase inhibitors are classified as reversible, irreversible, or quasi-irreversible (also called pseudo-irreversible).


An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. These agents inhibit parasympathetic nerve impulses by selectively blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells. The nerve fibers of the parasympathetic system are responsible for the involuntary movement of smooth muscles present in the gastrointestinal tract, urinary tract, lungs, and many other parts of the body. Anticholinergics are divided into three categories in accordance with their specific targets in the central and peripheral nervous system: antimuscarinic agents, ganglionic blockers, and neuromuscular blockers.


Bungarotoxins are a group of closely related neurotoxic proteins of the three-finger toxin superfamily found in the venom of kraits including Bungarus multicinctus. α-Bungarotoxin inhibits the binding of acetylcholine (ACh) to nicotinic acetylcholine receptors; β- and γ-bungarotoxins act presynaptically causing excessive acetylcholine release and subsequent depletion. Both α and β forms have been characterized, the α being similar to the long or Type II neurotoxins from other elapid venoms.

There are four types:






Butyrylcholine is a choline-based ester that can function as a neurotransmitter. It is similar to acetylcholine, with activation of some of the same receptors as acetylcholine. Butyrylcholine is a synthetic compound and does not occur in the body naturally. It is used as a clinical laboratory tool to distinguish between the cholinesterases; acetylcholinesterase and butyrylcholinesterase preferentially lyse acetylcholine and butyrylcholine, respectively.


In general, the word choline refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin. Choline also prevents fat deposits in the liver and facilitates the movement of fats into cells. The richest nutritional sources of choline are liver, kidney, brain, wheat germ, brewer's yeast, and egg yolk. Neurologically, cholinergic is the abbreviated term referring to acetylcholine (the suffix -ergic means stimulating; abbreviated ACh). The parasympathetic nervous system, which uses acetylcholine almost exclusively to send its messages, is said to be almost entirely cholinergic. Neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem complexes are also cholinergic. In addition, the receptor for the merocrine sweat glands are also cholinergic, since acetylcholine is released from postganglionic sympathetic neurons.

In neuroscience and related fields, the term cholinergic is used in these related contexts:

A substance (or ligand) is cholinergic if it is capable of producing, altering, or releasing acetylcholine ("indirect-acting") or mimicking its behaviour at one or more of the body's acetylcholine receptor types ("direct-acting"). Such mimics are called parasympathomimetic drugs or cholinomimetic drugs.

A receptor is cholinergic if it uses acetylcholine as its neurotransmitter.

A synapse is cholinergic if it uses acetylcholine as its neurotransmitter.


In biochemistry, a cholinesterase or choline esterase is an esterase that lyses choline-based esters, several of which serve as neurotransmitters. Thus, it is either of two enzymes that catalyze the hydrolysis of these cholinergic neurotransmitters, such as breaking acetylcholine into choline and acetic acid. These reactions are necessary to allow a cholinergic neuron to return to its resting state after activation. For example, in muscle contraction, acetylcholine at a neuromuscular junction triggers a contraction; but for the muscle to relax afterward, rather than remaining locked in a tense state, the acetylcholine must be broken down by a choline esterase. The main type for that purpose is acetylcholinesterase (also called choline esterase I or erythrocyte cholinesterase); it is found mainly in chemical synapses and red blood cell membranes. The other type is butyrylcholinesterase (also called choline esterase II or plasma cholinesterase); it is found mainly in the blood plasma.


Hexamethonium is a non-depolarising ganglionic blocker, a nicotinic nACh (NN) receptor antagonist that acts in autonomic ganglia by binding mostly in or on the NN receptor, and not the acetylcholine binding site itself. It does not have any effect on the muscarinic acetylcholine receptors (mAChR) located on target organs of the parasympathetic nervous system but acts as antagonist at the nicotinic acetylcholine receptors located in sympathetic and parasympathetic ganglia (NN).

Muscarinic acetylcholine receptor

Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.

Muscarinic receptors are so named because they are more sensitive to muscarine than to nicotine. Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpine and scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists.

Muscarinic acetylcholine receptor M1

The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor that in humans is encoded by the CHRM1 gene. It is localized to 11q13.This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve, is common in exocrine glands and in the CNS.It is predominantly found bound to G proteins of class Gq that use upregulation of phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signalling pathway. A receptor so bound would not be susceptible to CTX or PTX. However, Gi (causing a downstream decrease in cAMP) and Gs (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be susceptible to PTX and CTX respectively.

Muscarinic acetylcholine receptor M2

The muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2, is a muscarinic acetylcholine receptor that in humans is encoded by the CHRM2 gene. Multiple alternatively spliced transcript variants have been described for this gene.

Muscarinic acetylcholine receptor M3

The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M3, or the muscarinic 3, is a muscarinic acetylcholine receptor encoded by the human gene CHRM3.The M3 muscarinic receptors are located at many places in the body, e.g., smooth muscles, the endocrine glands, the exocrine glands, lungs, pancreas and the brain. In the CNS, they induce emesis. Muscarinic M3 receptors are expressed in regions of the brain that regulate insulin homeostasis, such as the hypothalamus and dorsal vagal complex of the brainstem. These receptors are highly expressed on pancreatic beta cells and are critical regulators of glucose homoestasis by modulating insulin secretion. In general, they cause smooth muscle contraction and increased glandular secretions.They are unresponsive to PTX and CTX.

Muscarinic acetylcholine receptor M4

The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene.

Muscarinic acetylcholine receptor M5

The human muscarinic acetylcholine receptor M5, encoded by the CHRM5 gene, is a member of the G protein-coupled receptor superfamily of integral membrane proteins. It is coupled to Gq protein. Binding of the endogenous ligand acetylcholine to the M5 receptor triggers a number of cellular responses such as adenylate cyclase inhibition, phosphoinositide degradation, and potassium channel modulation. Muscarinic receptors mediate many of the effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor have not been fully explored; however, stimulation of this receptor is known to effectively decrease cyclic AMP levels and downregulate the activity of protein kinase A (PKA).

Neuromuscular junction

A neuromuscular junction (or myoneural junction) is a chemical synapse formed by the contact between a motor neuron and a muscle fiber. It is at the neuromuscular junction that a motor neuron is able to transmit a signal to the muscle fiber, causing muscle contraction.

Muscles require innervation to function—and even just to maintain muscle tone, avoiding atrophy. Synaptic transmission at the neuromuscular junction begins when an action potential reaches the presynaptic terminal of a motor neuron, which activates voltage-dependent calcium channels to allow calcium ions to enter the neuron. Calcium ions bind to sensor proteins (synaptotagmin) on synaptic vesicles, triggering vesicle fusion with the cell membrane and subsequent neurotransmitter release from the motor neuron into the synaptic cleft. In vertebrates, motor neurons release acetylcholine (ACh), a small molecule neurotransmitter, which diffuses across the synaptic cleft and binds to nicotinic acetylcholine receptors (nAChRs) on the cell membrane of the muscle fiber, also known as the sarcolemma. nAChRs are ionotropic receptors, meaning they serve as ligand-gated ion channels. The binding of ACh to the receptor can depolarize the muscle fiber, causing a cascade that eventually results in muscle contraction.

Neuromuscular junction diseases can be of genetic and autoimmune origin. Genetic disorders, such as Duchenne muscular dystrophy, can arise from mutated structural proteins that comprise the neuromuscular junction, whereas autoimmune diseases, such as myasthenia gravis, occur when antibodies are produced against nicotinic acetylcholine receptors on the sarcolemma.

Nicotinic acetylcholine receptor

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs, including the nicotinic receptor agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms, including humans. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.The nicotinic receptors are considered cholinergic receptors, since they respond to acetylcholine. Nicotinic receptors get their name from nicotine, which does not stimulate the muscarinic acetylcholine receptor, but instead selectively binds to the nicotinic receptor. The muscarinic acetylcholine receptor likewise gets its name from a chemical that selectively attaches to that receptor — muscarine. Acetylcholine itself binds to both muscarinic and nicotinic acetylcholine receptors.

As ionotropic receptors, nAChRs are directly linked to ion channels. New evidence suggests that these receptors can also use second messengers (as metabotropic receptors do) in some cases. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors.Since nicotinic receptors help transmit outgoing signals for the sympathetic and parasympathetic systems, nicotinic receptor antagonists such as hexamethonium interfere with the transmission of these signals. Thus, for example, nicotinic receptor antagonists interfere with the baroreflex that normally corrects changes in blood pressure by sympathetic and parasympathetic stimulation of the heart.

Parasympathomimetic drug

A parasympathomimetic drug, sometimes called a cholinomimetic drug, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because acetylcholine (ACh) is the neurotransmitter used by the PSNS. Chemicals in this family can act either directly by stimulating the nicotinic or muscarinic receptors (thus mimicking acetylcholine), or indirectly by inhibiting cholinesterase, promoting acetylcholine release, or other mechanisms.Some chemical weapons such as sarin or VX, non-lethal riot control agents such as tear gas, and insecticides such as diazinon fall into this category.

Vesicular acetylcholine transporter

The Vesicular acetylcholine transporter (VAChT) is a neurotransmitter transporter which is responsible for loading acetylcholine (ACh) into secretory organelles in neurons making acetylcholine available for secretion. It is encoded by Solute carrier family 18, member 3 (SLC18A3) gene, located within the first intron of the choline acetyltransferase gene. VAChT is able to transport ACh into vesicles by relying on an exchange between protons (H+) that were previously pumped into the vesicle diffusing out, thus acting as an antiporter. ACh molecules are then carried into the vesicle by the action of exiting protons. Acetylcholine transport utilizes a proton gradient established by a vacuolar ATPase.

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