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Nicotinic acetylcholine receptor

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Acetylcholine
Nicotine

Nicotinic acetylcholine receptors,ornAChRs,arereceptorpolypeptidesthat respond to the neurotransmitteracetylcholine.Nicotinic receptors also respond to drugs such as the agonistnicotine.They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At theneuromuscular junctionthey are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In theperipheral nervous system:(1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within thesympatheticandparasympathetic 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.[1]Ininsects,thecholinergicsystem is limited to thecentral nervous system.[2]

The nicotinic receptors are consideredcholinergic receptors,since they respond to acetylcholine. Nicotinic receptors get their name fromnicotinewhich does not stimulate themuscarinic acetylcholine receptorsbut selectively binds to the nicotinic receptors instead.[3][4][5]The muscarinic acetylcholine receptor likewise gets its name from a chemical that selectively attaches to that receptor—muscarine.[6]Acetylcholine itself binds to both muscarinic and nicotinic acetylcholine receptors.[7]

Asionotropicreceptors, nAChRs are directly linked to ion channels. New evidence suggests that these receptors can also usesecond messengers(asmetabotropic receptorsdo) in some cases.[8]Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors.[3]

Since nicotinic receptors help transmit outgoing signals for the sympathetic and parasympathetic systems, nicotinic receptor antagonists such ashexamethoniuminterfere with the transmission of these signals. Thus, for example, nicotinic receptor antagonists interfere with thebaroreflex[9]that normally corrects changes in blood pressure by sympathetic and parasympathetic stimulation of the heart.

Structure[edit]

Nicotinic receptor structure

Nicotinic receptors, with a molecular mass of 290kDa,[10]are made up of five subunits, arranged symmetrically around a centralpore.[3]Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. They possess similarities withGABAAreceptors,glycine receptors,and the type 3serotonin receptors(which are all ionotropic receptors), or the signatureCys-loop proteins.[11]

In vertebrates, nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression:muscle-typenicotinic receptors andneuronal-typenicotinic 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).[3][4][5][12]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−α10and 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 thehydrophobicregions.[13]

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.[10][14][15][16]

Binding[edit]

For ligands, seeNicotinic agonistandNicotinic antagonist.

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 asligand,agonist, or transmitter. As well as the endogenous agonistacetylcholine,agonists of the nAChRincludenicotine,epibatidine,andcholine.Nicotinic antagonists that block the receptor include mecamylamine, dihydro-β-erythroidine, andhexamethonium.[13]

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 α7receptors. The binding site is located in the extracellular domain near theN terminus.[4][17]When an agonist binds to the site, all present subunits undergo a conformational change and the channel is opened[18]and a pore with a diameter of about 0.65 nm opens.[4]

Channel opening[edit]

Nicotinic AChRs may exist in different interconvertible conformational states. Binding of an agonist stabilizes the open anddesensitizedstates. In normal physiological conditions, the receptor needs exactly two molecules of ACh to open.[19]Opening of the channel allows positively chargedionsto move across it; in particular,sodiumenters the cell andpotassiumexits. 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.[3]It is permeable to Na+and K+,with some subunit combinations that are also permeable to Ca2+.[4][20][21]The amount of sodium and potassium the channels allow through their pores (theirconductance) varies from 50 to 110pS,with the conductance depending on the specific subunit composition as well as the permeant ion.[22]

Many neuronal nAChRs can affect the release of other neurotransmitters.[5]The channel usually opens rapidly and tends to remain open until theagonistdiffusesaway, which usually takes about 1millisecond.[4]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.[23][18]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 thesnake venomα-neurotoxins.These α-neurotoxinsantagonistically 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 usingnormal modedynamics[24]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 ofα-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.[25]

Effects[edit]

The activation of receptors by nicotine modifies the state ofneuronsthrough two main mechanisms. On one hand, the movement ofcationscauses adepolarizationof the plasma membrane (which results in anexcitatory postsynaptic potentialinneurons) leading to the activation ofvoltage-gated ion channels.On the other hand, the entry of calcium acts, either directly or indirectly, on differentintracellular cascades.This leads, for example, to the regulation of activity of somegenesor the release ofneurotransmitters.[citation needed]

Regulation[edit]

Desensitization[edit]

Ligand-bound desensitization of receptors was first characterized by Katz and Thesleff in the nicotinic acetylcholine receptor.[26]

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[27]by the activation of second messenger-dependent protein kinases.PKA[26]andPKC,[28]as well as tyrosine kinases,[29]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.[30]

Desensitized receptors can revert to a prolonged open state when an agonist is bound in the presence of a positive allosteric modulator, for examplePNU-120,596.[31]Also, there is evidence that indicates specific chaperone molecules have regulatory effects on these receptors.[32]

Roles[edit]

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 theLigand-Gated Ion Channel database). These receptors, with highly variablekinetic,electrophysiologicalandpharmacologicalproperties, respond tonicotinedifferently, at very different effective concentrations. This functional diversity allows them to take part in two major types of neurotransmission. Classicalsynaptic transmission(wiring transmission) involves the release of high concentrations of neurotransmitter, acting on immediately neighboring receptors. In contrast,paracrinetransmission (volume transmission) involvesneurotransmittersreleased byaxon terminals,which then diffuse through the extra-cellular medium until they reach their receptors, which may be distant.[33]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[34]where they can influence the release of multiple neurotransmitters.

Subunits[edit]

17 vertebrate nAChR subunits have been identified, which are divided into muscle-type and neuronal-type subunits. Although an α8subunit/gene is present in avian species such as the chicken, it is not present in human or mammalian species.[35]

The nAChR subunits have been divided into four subfamilies (I–IV) based on similarities in protein sequence.[36]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

Neuronal nAChRs aretransmembrane proteinsthat formpentameric structuresassembled from a family of subunits composed of α2–α10and β2–β4.[37]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(α8only found in chickens) and β2–β4.[38]It has also been discovered that various subunit combinations could form functional nAChRs that could be activated byacetylcholineandnicotine,and the different combinations of subunits generate subtypes of nAChRs with diverse functional and pharmacological properties.[39]When expressed alone, α7,α8,α9,and α10are able to form functional receptors, but other α subunits require the presence of β subunits to form functional receptors.[37]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. β2subunit-containing nAChRs (β2nAChRs) and α7nAChRs are widely expressed in the brain, whereas other nAChR subunits have more restricted expression.[40]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.[41]

CHRNA5/A3/B4[edit]

An important nAchR gene cluster (CHRNA5/A3/B4) contains the genes encoding for theα5,α3 and β4subunits. Genetic studies have identifiedsingle nucleotide polymorphisms (SNPs)in the chromosomal locus encoding these three nAChR genes as risk factors fornicotine dependence,lung cancer,chronic obstructive pulmonary disease,alcoholism,andperipheral arterial disease.[37][42]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 theperipheral nervous system (PNS)and other keycentral nervous system (CNS)sites, such as the medialhabenula,a structure between the limbic forebrain and midbrain involved in major cholinergic circuitry pathways.[37]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.[43]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.[37]

CHRNA6/CHRNB3[edit]

CHRNB3 and CHRNA6 are also grouped in a gene cluster, located on 8p11.[42]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.[42]Genetic variation in this region also displays influence susceptibility to use drugs of abuse, including cocaine and alcohol consumption.[44]Nicotinic receptors containing α6or β3subunits expressed in brain regions, especially in theventral tegmental areaandsubstantia nigra,are important for drug behaviors due to their role indopaminerelease.[45]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.[44]

CHRNA4/CHRNB2[edit]

Other well studied nAChR genes include the CHRNA4 and CHRNB2, which have been associated asAutosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE)genes.[42][46]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.[46][47]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.[42][46]

CHRNA7[edit]

Several studies have reported an association between CHRNA7 andendophenotypesof psychiatric disorders and nicotine dependence, contributing to the significant clinical relevance of α7and research being done on it.[46]CHRNA7 was one of the first genes that had been considered to be involved withschizophrenia.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.[46]Both nAChRs subtypes, α4β2and α7,have been found to be significantly reduced in post-mortem studies of individuals with schizophrenia.[48]Additionally, smoking rates are significantly higher in those with schizophrenia, implying that smoking nicotine may be a form of self-medicating.[49]

Notable variations[edit]

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).[50]A comparison follows:

Receptor-type Location Effect; functions Nicotinic agonists Nicotinic antagonists
Muscle-type:
(α1)2β1δε[50]
or
(α1)2β1δγ 		Neuromuscular junction EPSP,mainly by increasedNa+andK+permeability
Ganglion-type:
(α3)2(β4)3 		autonomic ganglia EPSP,mainly by increasedNa+andK+permeability
Heteromeric CNS-type:
(α4)2(β2)3 		Brain Post-andpresynaptic excitation,[50]mainly by increasedNa+andK+permeability. Major subtype involved in the attention-enhancing andrewardingeffects of nicotine as well as thepathophysiologyof nicotine addiction.[52][53][54]
Further CNS-type:
(α3)2(β4)3
 Brain Post-andpresynaptic excitation
Homomeric CNS-type:
(α7)5
 Brain Post-andpresynaptic excitation,[50]mainly by increasedNa+,K+andCa2+permeability. Major subtype involved in some of the cognitive effects of nicotine.[55]Moreover, activation of(α7)5could improve neurovascular coupling response in neurodegenerative disease[56]and neurogenesis in ischemic stroke.[57]Also involved in the pro-angiogenic effects of nicotine and accelerate the progression of chronic kidney disease in smokers.[58][59][60]

See also[edit]

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External links[edit]

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