
An acetylcholine receptor (abbreviated AChR) is an
integral membrane protein that responds to the binding of
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
, a
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
.
Classification
Like other
transmembrane receptors, acetylcholine receptors are classified according to their "pharmacology," or according to their relative affinities and sensitivities to different molecules. Although all acetylcholine receptors, by definition, respond to acetylcholine, they respond to other molecules as well.
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Nicotinic acetylcholine receptors (''nAChR'', also known as "
ionotropic" acetylcholine receptors) are particularly responsive to
nicotine
Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used fo ...
. The nicotine ACh receptor is also a Na
+, K
+ and Ca
2+ ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
.
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Muscarinic acetylcholine receptors (''mAChR'', also known as "
metabotropic" acetylcholine receptors) are particularly responsive to
muscarine.
Nicotinic and muscarinic are two main kinds of "cholinergic" receptors.
Receptor types
Molecular biology has shown that the nicotinic and muscarinic receptors belong to distinct
protein superfamilies
A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similari ...
. Nicotinic receptors are of two types: Nm and Nn. Nm is located in the neuromuscular junction which causes the contraction of skeletal muscles by way of
end-plate potential (EPPs). Nn causes depolarization in autonomic ganglia resulting in post ganglionic impulse. Nicotinic receptors cause the release of catecholamine from the adrenal medulla, and also site specific excitation or inhibition in brain. Both Nm and Nn are Na
+ and Ca
2+ channel linked but Nn is also linked with an extra K
+ channel.
nAChR
The nAChRs are
ligand -gated ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
s, and, like other members of the "
cys-loop"
ligand-gated ion channel superfamily, are composed of five
protein subunit
In structural biology, a protein subunit is a polypeptide chain or single protein molecule that assembles (or "''coassembles''") with others to form a protein complex.
Large assemblies of proteins such as viruses often use a small number of ty ...
s symmetrically arranged like staves around a barrel. The subunit composition is highly variable across different tissues. Each subunit contains four regions which span the membrane and consist of approximately 20 amino acids. Region II which sits closest to the pore lumen, forms the pore lining.
Binding of acetylcholine to the N termini of each of the two alpha subunits results in the 15° rotation of all M2 helices.
The cytoplasm side of the nAChR receptor has rings of high negative charge that determine the specific cation specificity of the receptor and remove the hydration shell often formed by ions in aqueous solution. In the intermediate region of the receptor, within the pore lumen,
valine and
leucine residues (Val 255 and Leu 251) define a hydrophobic region through which the dehydrated ion must pass.
The nAChR is found at the edges of junctional folds at the
neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
on the postsynaptic side; it is activated by
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
release across the synapse. The diffusion of Na
+ and K
+ across the receptor causes depolarization, the end-plate potential, that opens
voltage-gated sodium channels, which allows for firing of the
action potential and potentially muscular contraction.
mAChR
In contrast, the
mAChRs are not ion channels, but belong instead to the superfamily of
G-protein-coupled receptors that activate other ionic channels via a
second messenger
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
cascade.
The muscarine cholinergic receptor activates a G-protein when bound to extracellular ACh. The alpha subunit of the G-protein activates guanylate cyclase (inhibiting the effects of intracellular cAMP) while the beta-gamma subunit activates the K-channels and therefore hyperpolarize the cell. This causes a decrease in cardiac activity.
Origin and evolution
ACh receptors are related to
GABA,
glycine, and
5-HT3 receptor
The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs) and therefore differs structurally and functionally from all other 5-HT receptors (5-hydroxytryptamine, or serotonin receptors) which are G protein-coupled ...
s and their similar protein sequence and gene structure strongly suggest that they evolved from a common ancestral receptor. In fact, relatively minor mutations, such as a change in 3 amino acids in many of these receptors can convert a cation-selective channel to an anion-selective channel gated by acetylcholine, showing that even fundamental properties can relatively easily change in evolution.
Pharmacology
Acetylcholine receptor modulators can be classified by which receptor subtypes they act on:
Role in health and disease
Nicotinic acetylcholine receptors can be blocked by
curare,
hexamethonium and toxins present in the venoms of
snakes and
shellfish
Shellfish is a colloquial and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater envir ...
es, like
α-bungarotoxin. Drugs such as the
neuromuscular blocking agents bind reversibly to the nicotinic receptors in the
neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
and are used routinely in anaesthesia. Nicotinic receptors are the primary mediator of the effects of
nicotine
Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used fo ...
. In
myasthenia gravis
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, dro ...
, the receptor at the neuromuscular junction is targeted by
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
, leading to muscle weakness.
Muscarinic acetylcholine receptors can be blocked by the drugs
atropine
Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given i ...
and
scopolamine
Scopolamine, also known as hyoscine, or Devil's Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion sickness and postoperative nausea and vomiting ...
.
Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the
neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in nicotinic acetylcholine receptors. The majority of mutations causing CMS are found in the AChR subunits genes.
Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult acetylcholine receptor subunits. Mutations of the AChR often result in endplate deficiency. Most of the mutations of the AChR are mutations of the
CHRNE
Acetylcholine receptor subunit epsilon is a protein that in humans is encoded by the ''CHRNE'' gene.
Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of tw ...
gene with mutations encoding for the
Alpha5 Nicotinic Acetylcholine Receptor cause increased susceptibility to addiction. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR. One type of mutation of the epsilon subunit of the AChR introduces an Arg into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced ARG is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS.
See also
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Muscarinic acetylcholine receptor M5
The human muscarinic acetylcholine receptor M5, encoded by the 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 r ...
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Nicotinic agonists
References
External links
Acetylcholine receptor PMAP
The Proteolysis Map-animation
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Acetylcholine Receptor Molecule of The Month by David Goodsell
Acetylcholine receptors: muscarinic and nicotinicby Flavio Guzman
ANS receptors-overview
{{Acetylcholine receptor modulators
Integral membrane proteins
Molecular neuroscience