Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. 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.<ref>Template:Cite journal</ref> In insects, the cholinergic system is limited to the central nervous system.<ref name=Yamamoto1>Template:Cite book</ref>
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 receptors but selectively binds to the nicotinic receptors instead.<ref name="Purves" /><ref name="Siegel">Template:Cite book</ref><ref name="Itier">Template:Cite journal</ref> The muscarinic acetylcholine receptor likewise gets its name from a chemical that selectively attaches to that receptor—muscarine.<ref name="pmid17073660">Template:Cite journal</ref> Acetylcholine itself binds to both muscarinic and nicotinic acetylcholine receptors.<ref name="Cholinergic Toxicity">Template:Cite book</ref>
As ionotropic receptors, nAChRs are directly linked to ion channels. Some evidence suggests that these receptors can also use second messengers (as metabotropic receptors do) in some cases.<ref>Template:Cite journal</ref> Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors.<ref name="Purves" >Template:Cite book</ref>
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<ref>Template:Cite journal</ref> that normally corrects changes in blood pressure by sympathetic and parasympathetic stimulation of the heart.
StructureEdit
Nicotinic receptors, with a molecular mass of 290 kDa,<ref name="Unwin">Template:Cite journal</ref> are made up of five subunits, arranged symmetrically around a central pore.<ref name="Purves" /> Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. They possess similarities with GABAA receptors, glycine receptors, and the type 3 serotonin receptors (which are all ionotropic receptors), or the signature Cys-loop proteins.<ref name="Cascio">Template:Cite journal</ref>
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 α1, β1, γ, and δ subunits in a 2:1:1:1 ratio ((α1)2β1γδ), or the adult form composed of α1, β1, δ, and ε subunits in a 2:1:1:1 ratio ((α1)2β1δε).<ref name="Purves" /><ref name="Siegel"/><ref name="Itier"/><ref name="Giniatullin">Template:Cite journal</ref> 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: α2−α10 and β2−β4. Examples of the neuronal subtypes include: (α4)3(β2)2, (α4)2(β2)3, (α3)2(β4)3, α4α6β3(β2)2, (α7)5, and many others. In both muscle-type and neuronal-type receptors, the subunits are very similar to one another, especially in the hydrophobic regions.<ref name=":0" />
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.<ref name="Unwin"/><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
BindingEdit
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, agonist, or transmitter. As well as the endogenous agonist acetylcholine, agonists of the nAChR include nicotine, epibatidine, and choline. Nicotinic antagonists that block the receptor include mecamylamine, dihydro-β-erythroidine, α-bungarotoxin, and hexamethonium.<ref name=":0">Template:Cite journal</ref><ref>Template:Cite journal</ref>
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 α7 receptors. The binding site is located in the extracellular domain near the N terminus.<ref name="Siegel"/><ref>Template:Cite book</ref> When an agonist binds to the site, all present subunits undergo a conformational change and the channel is opened<ref name="Colquhoun">Template:Cite journal</ref> and a pore with a diameter of about 0.65 nm opens.<ref name="Siegel"/>
Channel openingEdit
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.<ref>Template:Cite bookTemplate:Page needed</ref> Opening of the channel allows positively charged ions to move across it; in particular, sodium enters the cell and potassium 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.<ref name="Purves" /> It is permeable to Na+ and K+, with some subunit combinations that are also permeable to Ca2+.<ref name="Siegel" /><ref name="Beker_AChR_Ca2+">Template:Cite journal</ref><ref name="Weber_nAChR_anaesthetics">Template:Cite journal</ref> The amount of sodium and potassium the channels allow through their pores (their conductance) varies from 50 to 110 pS, with the conductance depending on the specific subunit composition as well as the permeant ion.<ref name="Mishina">Template:Cite journal</ref>
Many neuronal nAChRs can affect the release of other neurotransmitters.<ref name="Itier" /> The channel usually opens rapidly and tends to remain open until the agonist diffuses away, which usually takes about 1 millisecond.<ref name="Siegel" /> 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.<ref>Template:Cite journal</ref><ref name="Colquhoun"/> 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 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 dynamics<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>
EffectsEdit
The activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movement of cations causes a depolarization of the plasma membrane (which results in an excitatory postsynaptic potential in neurons) leading to the activation of voltage-gated ion channels. 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 genes or the release of neurotransmitters.Template:Citation needed
RegulationEdit
DesensitizationEdit
Ligand-bound desensitization of receptors was first characterized by Katz and Thesleff in the nicotinic acetylcholine receptor.<ref name="P1983">Template:Cite journal</ref>
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<ref name="pmid6302672">Template:Cite journal</ref> by the activation of second messenger-dependent protein kinases. PKA<ref name=P1983/> and PKC,<ref name="pmid3038884">Template:Cite journal</ref> as well as tyrosine kinases,<ref>Template:Cite journal</ref> 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.<ref name="pmid712829">Template:Cite journal</ref>
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.<ref name="pmid15858066">Template:Cite journal</ref> Also, there is evidence that indicates specific chaperone molecules have regulatory effects on these receptors.<ref name="pmid25771456">Template:Cite journal</ref>
RolesEdit
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 the Ligand-Gated Ion Channel database). These receptors, with highly variable kinetic, electrophysiological and pharmacological properties, respond to nicotine differently, at very different effective concentrations. This functional diversity allows them to take part in two major types of neurotransmission. Classical synaptic transmission (wiring transmission) involves the release of high concentrations of neurotransmitter, acting on immediately neighboring receptors. In contrast, paracrine transmission (volume transmission) involves neurotransmitters released by axon terminals, which then diffuse through the extra-cellular medium until they reach their receptors, which may be distant.<ref>Template:Cite journal</ref> 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<ref name="pmid9023878">Template:Cite journal</ref> where they can influence the release of multiple neurotransmitters. Nicotine addiction arises from nAChR-mediated dopamine release in the mesolimbic pathway.
SubunitsEdit
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.<ref name="pmid12150770">Template:Cite journal</ref>
The nAChR subunits have been divided into four subfamilies (I–IV) based on similarities in protein sequence.<ref name="pmid7699721">Template:Cite journal</ref> In addition, subfamily III has been further divided into three types.
| Neuronal-type | Muscle-type | ||||
| I | II | III | IV | ||
|---|---|---|---|---|---|
| α9, α10 | α7, α8 | 1 | 2 | 3 | α1, β1, δ, γ, ε |
| α2, α3, α4, α6 | β2, β4 | β3, α5 | |||
- α genes: Template:Gene (muscle), Template:Gene (neuronal), Template:Gene, Template:Gene, Template:Gene, Template:Gene, Template:Gene, Template:Gene, Template:Gene, Template:Gene
- β genes: Template:Gene (muscle), Template:Gene (neuronal), Template:Gene, Template:Gene
- Other genes: Template:Gene (delta), Template:Gene (epsilon), Template:Gene (gamma)
Neuronal nAChRs are transmembrane proteins that form pentameric structures assembled from a family of subunits composed of α2–α10 and β2–β4.<ref name="Improgo et al 2010">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> It has also been discovered that various subunit combinations could form functional nAChRs that could be activated by acetylcholine and nicotine, and the different combinations of subunits generate subtypes of nAChRs with diverse functional and pharmacological properties.<ref>Template:Cite journal</ref> 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.<ref name="Improgo et al 2010"/> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>
CHRNA5/A3/B4Edit
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, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease.<ref name="Improgo et al 2010"/><ref name="Greenbaum & Lerer 2009"/> 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, a structure between the limbic forebrain and midbrain involved in major cholinergic circuitry pathways.<ref name="Improgo et al 2010"/> 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.<ref>Template:Cite journal</ref> 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.<ref name="Improgo et al 2010"/>
CHRNA6/CHRNB3Edit
CHRNB3 and CHRNA6 are also grouped in a gene cluster, located on 8p11.<ref name="Greenbaum & Lerer 2009"/> 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.<ref name="Greenbaum & Lerer 2009"/> Genetic variation in this region also displays influence susceptibility to use drugs of abuse, including cocaine and alcohol consumption.<ref name="Kamens et al 2016">Template:Cite journal</ref> Nicotinic receptors containing α6 or β3 subunits expressed in brain regions, especially in the ventral tegmental area and substantia nigra, are important for drug behaviors due to their role in dopamine release.<ref>Template:Cite journal</ref> 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.<ref name="Kamens et al 2016"/>
CHRNA4/CHRNB2Edit
Other well studied nAChR genes include the CHRNA4 and CHRNB2, which have been associated as Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) genes.<ref name="Greenbaum & Lerer 2009"/><ref name="Steinlein & Bertrand 2008">Template:Cite journal</ref> Both of these nAChR subunits are present in the brain and the occurrence of mutations in these two subunits cause a focal 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.<ref name="Steinlein & Bertrand 2008"/><ref>Template:Cite journal</ref> 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.<ref name="Greenbaum & Lerer 2009">Template:Cite journal</ref><ref name="Steinlein & Bertrand 2008"/>
CHRNA7Edit
Several studies have reported an association between CHRNA7 and endophenotypes of psychiatric disorders and nicotine dependence, contributing to the significant clinical relevance of α7 and research being done on it.<ref name="Steinlein & Bertrand 2008"/> CHRNA7 was one of the first genes that had been considered to be involved with schizophrenia. 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.<ref name="Steinlein & Bertrand 2008"/> Both nAChRs subtypes, α4β2 and α7, have been found to be significantly reduced in post-mortem studies of individuals with schizophrenia.<ref>Template:Cite journal</ref> Additionally, smoking rates are significantly higher in those with schizophrenia, implying that smoking nicotine may be a form of self-medicating.<ref>Template:Cite journal</ref> CHRNA7 has also been shown to modulate immune responses though cholinergic anti-inflammatory pathway (CAP).<ref>Template:Cite journal</ref>
Notable variationsEdit
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).<ref name=Rang>Template:Cite bookTemplate:Page needed</ref> A comparison follows:
| Receptor-type | Location | Effect; functions | Nicotinic agonists | Nicotinic antagonists | |
|---|---|---|---|---|---|
| Muscle-type: (α1)2β1δε<ref name=Rang/> or (α1)2β1δγ |
Neuromuscular junction | EPSP, mainly by increased Na+ and K+ permeability |
|
| |
| Ganglion-type: (α3)2(β4)3 |
autonomic ganglia | EPSP, mainly by increased Na+ and K+ permeability |
|
| |
| Heteromeric CNS-type: (α4)2(β2)3 |
Brain | Post- and presynaptic excitation,<ref name=Rang/> mainly by increased Na+ and K+ permeability. Major subtype involved in the attention-enhancing and rewarding effects of nicotine as well as the pathophysiology of nicotine addiction.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Nicotine IUPHAR">{{#invoke:citation/CS1|citation | CitationClass=web
}}</ref> |
||
| Further CNS-type: (α3)2(β4)3 |
Brain | Post- and presynaptic excitation | |||
| Homomeric CNS-type: (α7)5 |
Brain | Post- and presynaptic excitation,<ref name=Rang/> mainly by increased Na+, K+ and Ca2+ permeability. Major subtype involved in some of the cognitive effects of nicotine.<ref>Template:Cite journal</ref> Moreover, activation of (α7)5 could improve neurovascular coupling response in neurodegenerative disease<ref>Template:Cite journal</ref> and neurogenesis in ischemic stroke.<ref>Template:Cite journal</ref> Also involved in the pro-angiogenic effects of nicotine and accelerate the progression of chronic kidney disease in smokers.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="pmid16766716">Template:Cite journal</ref> |
|
See alsoEdit
- Muscarinic agonist
- Muscarinic antagonist
- TDBzcholine
- Myasthenia gravis
- Congenital myasthenic syndrome
- Adrenergic
- Adrenergic receptor
ReferencesEdit
External linksEdit
- Template:Commons category-inline
- Calculated spatial position of Nicotinic acetylcholine receptor in the lipid bilayer
Template:Autoantigens Template:Ligand-gated ion channels Template:Nicotinic acetylcholine receptor modulators