Nicotinic acetylcholine receptors, or nAChRs, are
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
polypeptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A p ...
s that respond to the neurotransmitter
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 ...
. Nicotinic receptors also respond to drugs such as the agonist
nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. 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 ...
they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the
sympathetic and
parasympathetic nervous system
The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...
, 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
insect
Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three pairs ...
s, the
cholinergic
Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation. F ...
system is limited to the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
.
The nicotinic receptors are considered
cholinergic receptors
An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
Classification
Like other transmembrane receptors, acetylcholine receptors are classified according ...
, since they respond to acetylcholine. Nicotinic receptors get their name from
nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
which does not stimulate the
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-rece ...
s but selectively binds to the nicotinic receptors instead.
The muscarinic acetylcholine receptor likewise gets its name from a chemical that selectively attaches to that receptor —
muscarine
Muscarine, L-(+)-muscarine, or muscarin is a natural product found in certain mushrooms, particularly in ''Inocybe'' and ''Clitocybe'' species, such as the deadly '' C. dealbata''. Mushrooms in the genera ''Entoloma'' and ''Mycena'' have al ...
.
Acetylcholine itself binds to both muscarinic and nicotinic acetylcholine receptors.
As
ionotropic
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...
receptors, nAChRs are directly linked to ion channels. New evidence suggests that these receptors can also use
second messengers
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 ...
(as
metabotropic receptor
A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor, is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity. The nervous system utilizes two types of receptors: met ...
s 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
Hexamethonium is a non-depolarising ganglionic blocker, a nicotinic ( nAChR) receptor antagonist that acts in autonomic ganglia by binding mostly in or on the nAChR receptor, and not the acetylcholine binding site itself. It does not have a ...
interfere with the transmission of these signals. Thus, for example, nicotinic receptor antagonists interfere with the
baroreflex
The baroreflex or
baroreceptor reflex is one of the body's homeostatic mechanisms that helps to maintain blood pressure at nearly constant levels. The baroreflex provides a rapid negative feedback loop in which an elevated blood pressure causes the ...
that normally corrects changes in blood pressure by sympathetic and parasympathetic stimulation of the heart.
Structure
![NAChR](https://upload.wikimedia.org/wikipedia/commons/1/13/NAChR.png)
Nicotinic receptors, with a molecular mass of 290
kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at ...
,
are made up of five subunits, arranged symmetrically around a central
pore
Pore may refer to:
Biology Animal biology and microbiology
* Sweat pore, an anatomical structure of the skin of humans (and other mammals) used for secretion of sweat
* Hair follicle, an anatomical structure of the skin of humans (and other m ...
.
Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. They possess similarities with
GABAA receptors,
glycine receptor
The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current. It is one of the most widely distributed inhibitory ...
s, and the type 3
serotonin receptor
5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neur ...
s (which are all ionotropic receptors), or the signature
Cys-loop protein The Cys-loop ligand-gated ion channel superfamily is composed of Nicotinic acetylcholine receptor, nicotinic acetylcholine, GABA A receptor, GABAA, GABAA-rho receptor, GABAA-ρ, Glycine receptor, glycine, 5-HT3 receptor, 5-HT3, and zinc-activated io ...
s.
In vertebrates, nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression: ''muscle-type'' nicotinic receptors and ''neuronal-type'' nicotinic receptors. In the muscle-type receptors, found at the neuromuscular junction, receptors are either the embryonic form, composed of α
1, β
1, γ, and δ subunits in a 2:1:1:1 ratio ((α
1)
2β
1γδ), or the adult form composed of α
1, β
1, δ, and ε subunits in a 2:1:1:1 ratio ((α
1)
2β
1δε).
The neuronal subtypes are various homomeric (all one type of subunit) or heteromeric (at least one α and one β) combinations of twelve different nicotinic receptor subunits: α
2−α
10 and β
2−β
4. Examples of the neuronal subtypes include: (α
4)
3(β
2)
2, (α
4)
2(β
2)
3, (α
3)
2(β
4)
3, α
4α
6β
3(β
2)
2, (α
7)
5, and many others. In both muscle-type and neuronal-type receptors, the subunits are very similar to one another, especially in the
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
regions.
A number of electron microscopy and x-ray crystallography studies have provided very high resolution structural information for muscle and neuronal nAChRs and their binding domains.
Binding
As with all ligand-gated ion channels, opening of the nAChR channel pore requires the binding of a chemical messenger. Several different terms are used to refer to the molecules that bind receptors, such as
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
, agonist, or transmitter. As well as the endogenous agonist
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 ...
,
agonists of the nAChR include
nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
,
epibatidine
Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog '' Epipedobates anthonyi'' and poison dart frogs from the Ameerega genus. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until ...
, and
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but re ...
. Nicotinic antagonists that block the receptor include mecamylamine, dihydro-β-erythroidine, and
hexamethonium
Hexamethonium is a non-depolarising ganglionic blocker, a nicotinic ( nAChR) receptor antagonist that acts in autonomic ganglia by binding mostly in or on the nAChR receptor, and not the acetylcholine binding site itself. It does not have a ...
.
In muscle-type nAChRs, the acetylcholine binding sites are located at the α and either ε or δ subunits interface. In neuronal nAChRs, the binding site is located at the interface of an α and a β subunit or between two α subunits in the case of α
7 receptors. The binding site is located in the extracellular domain near the
N terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
.
When an agonist binds to the site, all present subunits undergo a conformational change and the channel is opened
and a pore with a diameter of about 0.65 nm opens.
Channel opening
Nicotinic AChRs may exist in different interconvertible conformational states. Binding of an agonist stabilizes the open and
desensitized states. In normal physiological conditions, the receptor needs exactly two molecules of ACh to open. Opening of the channel allows positively charged
ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
s to move across it; in particular,
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
enters the cell and
potassium
Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...
exits. The net flow of positively charged ions is inward.
The nAChR is a non-selective cation channel, meaning that several different positively charged ions can cross through.
It is permeable to Na
+ and K
+, with some subunit combinations that are also permeable to Ca
2+.
The amount of sodium and potassium the channels allow through their pores (their
conductance) varies from 50–110
pS, with the conductance depending on the specific subunit composition as well as the permeant ion.
Many neuronal nAChRs can affect the release of other neurotransmitters.
The channel usually opens rapidly and tends to remain open until the
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
diffuses away, which usually takes about 1
millisecond
A millisecond (from '' milli-'' and second; symbol: ms) is a unit of time in the International System of Units (SI) equal to one thousandth (0.001 or 10−3 or 1/1000) of a second and to 1000 microseconds.
A unit of 10 milliseconds may be called ...
.
AChRs can spontaneously open with no ligands bound or can spontaneously close with ligands bound, and mutations in the channel can shift the likelihood of either event.
Therefore, ACh binding changes the probability of pore opening, which increases as more ACh binds.
The nAChR is unable to bind ACh when bound to any of the
snake venom
Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is injected by unique fangs during a bite, whereas some species are a ...
α-neurotoxins. These α-neurotoxins antagonistically bind tightly and noncovalently to nAChRs of skeletal muscles and in neurons, thereby blocking the action of ACh at the postsynaptic membrane, inhibiting ion flow and leading to paralysis and death. The nAChR contains two binding sites for snake venom neurotoxins. Progress in discovering the dynamics of binding action of these sites has proved difficult, although recent studies using
normal mode
A normal mode of a dynamical system is a pattern of motion in which all parts of the system move sinusoidally with the same frequency and with a fixed phase relation. The free motion described by the normal modes takes place at fixed frequencies. ...
dynamics have aided in predicting the nature of both the binding mechanisms of snake toxins and of ACh to nAChRs. These studies have shown that a twist-like motion caused by ACh binding is likely responsible for pore opening, and that one or two molecules of
α-bungarotoxin (or other long-chain α-neurotoxin) suffice to halt this motion. The toxins seem to lock together neighboring receptor subunits, inhibiting the twist and therefore, the opening motion.
Effects
The activation of receptors by nicotine modifies the state of
neurons
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
through two main mechanisms. On one hand, the movement of
cation
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
s causes a
depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
of the plasma membrane (which results in an
excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...
in
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s) leading to the activation of
voltage-gated ion channel
Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, ...
s. On the other hand, the entry of calcium acts, either directly or indirectly, on different
intracellular cascades. This leads, for example, to the regulation of activity of some
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s or the release of
neurotransmitters
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.
Neur ...
.
Regulation
Desensitization
Ligand-bound desensitization of receptors was first characterized by Katz and Thesleff in the nicotinic acetylcholine receptor.
Prolonged or repeated exposure to a stimulus often results in decreased responsiveness of that receptor toward a stimulus, termed desensitization. nAChR function can be modulated by phosphorylation
by the activation of second messenger-dependent protein kinases.
PKA
PKA may refer to:
* Professionally known as:
** Pen name
** Stage persona
* p''K''a, the symbol for the acid dissociation constant at logarithmic scale
* Protein kinase A, a class of cAMP-dependent enzymes
* Pi Kappa Alpha, the North-American so ...
[ and PKC,] as well as tyrosine kinases, have been shown to phosphorylate the nAChR resulting in its desensitization. It has been reported that, after prolonged receptor exposure to the agonist, the agonist itself causes an agonist-induced conformational change in the receptor, resulting in receptor desensitization.
Desensitized receptors can revert to a prolonged open state when an agonist is bound in the presence of a positive allosteric modulator, for example PNU-120,596
PNU-120596 is a drug that acts as a potent and selective positive allosteric modulator for the α7 subtype of neural nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to th ...
. Also, there is evidence that indicates specific chaperone molecules have regulatory effects on these receptors.
Roles
The subunits of the nicotinic receptors belong to a multigene family (16 members in humans) and the assembly of combinations of subunits results in a large number of different receptors (for more information see th
Ligand-Gated Ion Channel database
. These receptors, with highly variable kinetic
Kinetic (Ancient Greek: κίνησις “kinesis”, movement or to move) may refer to:
* Kinetic theory of gases, Kinetic theory, describing a gas as particles in random motion
* Kinetic energy, the energy of an object that it possesses due to i ...
, electrophysiological
Electrophysiology (from Greek , ''ēlektron'', "amber" etymology of "electron"">Electron#Etymology">etymology of "electron" , ''physis'', "nature, origin"; and , ''-logia'') is the branch of physiology that studies the electrical properties of bi ...
and pharmacological
Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
properties, respond to nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
differently, at very different effective concentrations. This functional diversity allows them to take part in two major types of neurotransmission. Classical synaptic transmission
Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
(wiring transmission) involves the release of high concentrations of neurotransmitter, acting on immediately neighboring receptors. In contrast, paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...
transmission (volume transmission) involves neurotransmitters
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.
Neur ...
released by axon terminals
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
, which then diffuse through the extra-cellular medium until they reach their receptors, which may be distant. Nicotinic receptors can also be found in different synaptic locations; for example the muscle nicotinic receptor always functions post-synaptically. The neuronal forms of the receptor can be found both post-synaptically (involved in classical neurotransmission) and pre-synaptically where they can influence the release of multiple neurotransmitters.
Subunits
17 vertebrate nAChR subunits have been identified, which are divided into muscle-type and neuronal-type subunits. Although an α8 subunit/gene is present in avian species such as the chicken, it is not present in human or mammalian species.
The nAChR subunits have been divided into 4 subfamilies (I–IV) based on similarities in protein sequence. In addition, subfamily III has been further divided into 3 types.
* α genes: (muscle), (neuronal), , , , , , , ,
* β genes: (muscle), (neuronal), ,
* Other genes: (delta), (epsilon), (gamma)
Neuronal nAChRs are transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
s that form pentameric structures assembled from a family of subunits composed of α2–α10 and β2–β4. These subunits were discovered from the mid-1980s through the early 1990s, when cDNAs for multiple nAChR subunits were cloned from rat and chicken brains, leading to the identification of eleven different genes (twelve in chickens) that code for neuronal nAChR subunits; The subunit genes identified were named α2–α10 (α8 only found in chickens) and β2–β4. It has also been discovered that various subunit combinations could form functional nAChRs that could be 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 ...
and nicotine
Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
, and the different combinations of subunits generate subtypes of nAChRs with diverse functional and pharmacological properties. When expressed alone, α7, α8, α9, and α10 are able to form functional receptors, but other α subunits require the presence of β subunits to form functional receptors. In mammals, nAchR subunits have been found to be encoded by 17 genes, and of these, nine genes encoding α-subunits and three encoding β-subunits are expressed in the brain. β2 subunit-containing nAChRs (β2nAChRs) and α7nAChRs are widely expressed in the brain, whereas other nAChR subunits have more restricted expression. The pentameric assembly of nAChRs is subjected to the subunits that are produced in various cell types such as in the human lung where epithelial and muscular pentamers largely differ.
CHRNA5/A3/B4
An important nAchR gene cluster (CHRNA5/A3/B4) contains the genes encoding for the α5, α3 and β4 subunits. Genetic studies have identified single nucleotide polymorphisms (SNPs) in the chromosomal locus encoding these three nAChR genes as risk factors for nicotine dependence
Nicotine dependence is a state of dependence upon nicotine. Nicotine dependence is a chronic, relapsing disease defined as a compulsive craving to use the drug, despite social consequences, loss of control over drug intake, and emergence of with ...
, lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...
, chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
, alcoholism
Alcoholism is, broadly, any drinking of alcohol (drug), alcohol that results in significant Mental health, mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognize ...
, and peripheral arterial disease
Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular diseas ...
. The CHRNA5/A3/B4 nAChR subunit genes are found in a tight cluster in chromosomal region 15q24–25. The nAChR subunits encoded by this locus form the predominant nicotinic receptor subtypes expressed in the peripheral nervous system (PNS) and other key central nervous system (CNS) sites, such as the medial habenula
In neuroanatomy, habenula (diminutive of Latin ''habena'' meaning rein) originally denoted the stalk of the pineal gland (pineal habenula; pedunculus of pineal body), but gradually came to refer to a neighboring group of nerve cells with which the ...
, a structure between the limbic forebrain and midbrain involved in major cholinergic circuitry pathways. Further research of the CHRNA5/A3/B4 genes have revealed that “neuronal” nAChR genes are also expressed in non-neuronal cells where they are involved in various fundamental processes, such as inflammation. The CHRNA5/A3/B4 genes are co-expressed in many cell types and the transcriptional activities of the promoter regions of the three genes are regulated by many of the same transcription factors, demonstrating that their clustering may reflect control of gene expression.
CHRNA6/CHRNB3
CHRNB3 and CHRNA6 are also grouped in a gene cluster, located on 8p11. Multiple studies have shown that SNPS in the CHRNB3–CHRNA6 have been linked to nicotine dependence and smoking behavior, such as two SNPs in CHRNB3, rs6474413 and rs10958726. Genetic variation in this region also displays influence susceptibility to use drugs of abuse, including cocaine and alcohol consumption. Nicotinic receptors containing α6 or β3 subunits expressed in brain regions, especially in the ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...
and substantia nigra
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...
, are important for drug behaviors due to their role in dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
release. Genetic variation in these genes can alter sensitivity to drugs of abuse in numerous ways, including changing the amino acid structure of the protein or cause alterations in transcriptional and translational regulation.
CHRNA4/CHRNB2
Other well studied nAChR genes include the CHRNA4 and CHRNB2, which have been associated as Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) genes. Both of these nAChR subunits are present in the brain and the occurrence of mutations in these two subunits cause a generalized type of epilepsy. Examples include the CHRNA4 insertion mutation 776ins3 that is associated with nocturnal seizures and psychiatric disorders, and the CHRNB2 mutation I312M that seems to cause not only epilepsy but also very specific cognitive deficits, such as deficits in learning and memory. There is naturally occurring genetic variation between these two genes and analysis of single nucleotide polymorphisms (SNPs) and other gene modifications show a higher variation in the CHRNA4 gene than in the CHRNB2 gene, implying that nAChR β2, the protein encoded by CHRNB2, associates with more subunits than α4. CHRNA2 has also been reported as a third candidate for nocturnal frontal lobe seizures.
CHRNA7
Several studies have reported an association between CHRNA7 and endophenotype In genetic epidemiology, endophenotype (or intermediate phenotype) is a term used to separate behavioral symptoms into more stable phenotypes with a clear genetic connection. The concept was coined by Bernard John and Kenneth R. Lewis in a 1966 pap ...
s of psychiatric disorders and nicotine dependence, contributing to the significant clinical relevance of α7 and research being done on it. CHRNA7 was one of the first genes that had been considered to be involved with schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
. Studies identified several CHRNA7 promoter polymorphisms that reduce the genes transcriptional activity to be associated with schizophrenia, which is consistent with the finding of reduced levels of a7 nAChRs in the brain of schizophrenic patients. Both nAChRs subtypes, α4β2 and α7, have been found to be significantly reduced in post-mortem studies of individuals with schizophrenia. Additionally, smoking rates are significantly higher in those with schizophrenia, implying that smoking nicotine may be a form of self-medicating.
Notable variations
Nicotinic receptors are pentamers of these subunits; i.e., each receptor contains five subunits. Thus, there is immense potential of variation of these subunits, some of which are more commonly found than others. The most broadly expressed subtypes include (α1)2β1δε (adult muscle-type), (α3)2(β4)3 (ganglion-type), (α4)2(β2)3 (CNS-type) and (α7)5 (another CNS-type). A comparison follows:
See also
* Muscarinic agonist
A muscarinic agonist is an agent that activates the activity of the muscarinic acetylcholine receptor. The muscarinic receptor has different subtypes, labelled M1-M5, allowing for further differentiation.
Clinical significance
M1
M1-type musca ...
* Muscarinic antagonist
A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the ...
* TDBzcholine
TDBzcholine is a diazirine analog of acetylcholine that can be used to label the nicotinic acetylcholine receptor.
Mechanism of action
TDBzcholine is able to bind to the nicotinic acetylcholine receptor. Once TDBzcholine is bound to the receptor, ...
References
External links
*
Calculated spatial position of Nicotinic acetylcholine receptor in the lipid bilayer
{{DEFAULTSORT:Nicotinic Acetylcholine Receptor
Ion channels
Autoantigens
Cell signaling
Acetylcholine receptors