Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Acetylcholine (Nicotinic) Receptor

  • Josephine R. Tarren
  • Joan Y. Holgate
  • Selena E. Bartlett
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101538

Synonyms

Historical Background

The pharmacological effects of nicotine have long been known, with nicotine first isolated from tobacco plants by Posselt and Reimann in 1828 (Albuquerque et al. 2009). The attempts to isolate the physiologic effect of nicotinic acetylcholine receptors (nAChRs) using the Torpedo organism have been traced back as far as 1885 (Paul Ehrlich) and 1857 (Claude Bernard). It was first proposed to be a protein in 1955 by David Nachmansohn and later biochemically characterized by Changeux, Kasai, and Lee in 1970. In 1983 it became the first ligand-gated ion channel for which the DNA and protein were further defined by using molecular genetics. (For more information on the history of the discovery of nAChRs see Martindale and Lester 2014.) Today, nAChRs are the most studied type of ionotropic receptor and have been identified in muscle, neuromuscular junctions, and the central nervous system (Albuquerque et al. 2009). Their subunits are encoded by 17 different genes (CHRNA1–10, CHRNB1–4, CHRND, CHRNE, CHRNG) and all but CHRNA8 (avian species only) are present in mammals (Albuquerque et al. 2009).

Structure

Neuronal nAChRs belong to a large superfamily of ligand-gated ionotropic receptors, which also include muscle-type acetylcholine receptors, γ-aminobutyric-A receptors (GABAA), and like most transmembrane proteins, nAChRs were named according to their distinct pharmacological binding properties. They respond primarily to the endogenous neurotransmitter acetylcholine (ACh) and have a high affinity for/are particularly sensitive to the parasympathomimetic stimulant, nicotine (Dani and Bertrand 2007). While the complete structure of each nAChR molecule is not yet resolved, methods such as x-ray crystallography, electron microscopy, and sequence analysis have detailed a relatively universal structure, derived significantly from purification of the Torpedo nAChR (Albuquerque et al. 2009). Like all other ligand-gated ion channels, nAChRs consist of a conserved extracellular N-terminal domain, a trans-membrane domain, and a cytoplasmic domain (Fig. 1). The hydrophilic extracellular amino acid terminal carries the ACh-binding site, aligning in a configuration termed the β-barrel, facing the synaptic cleft. This is followed by four prominent transmembrane hydrophobic α-helices (M1-M4), neatly assembled around the innermost hydrophilic pore (Albuquerque et al. 2009). These traverse the lipid bilayer, with mutagenesis experiments showing the M2 domain delineates the ion channel; while M4, relative to M2, is positioned to interact predominantly with the lipid bilayer and represents the receptor-lipid interface extending a variable extracellular COOH-terminal sequence. M1 and M3 are positioned opposite to one another, sitting 90° in relation to M2 and M4 (Albuquerque et al. 2009). The cytoplasmic domain, inserted between helices M3 and M4, is the most variable of the domains, and generally composed of both α-helical and β-strand edifices (Albuquerque et al. 2009; Taly et al. 2009).
Acetylcholine (Nicotinic) Receptor, Fig. 1

Structure of the nicotinic acetylcholine receptor. Schematic representation of (a) the five subunits (magenta, blue, green, peach, and yellow) and (b) the extracellular N-terminal, transmembrane, and cytoplasmic domains of the nAChR (Adapted from Fig. 1 in Alves (2014) under the Creative Commons licence (https://creativecommons.org/licenses/by/3.0/). Image has been cropped, cut, and pasted to the horizontal plan (Alves et al. 2014))

Neuronal nAChRs can take homomeric (α7–9) or heteromeric (α2–6, α10, and β1–4) forms and consist of a diverse range of subunits (Albuquerque et al. 2009). Initial classification showed that α subunits carry the primary Ach-binding site, with β subunits holding complementary components. All nine α subunits also exhibit adjacent cysteines, while β subunits do not (Albuquerque et al. 2009). In the case of homologous systems, each subunit contributes both the primary and complementary binding components. Aside from this, when expressed alone α5 and β3 lack functionality and α10 must be expressed with α9. It is presumed that both conformation types (heteromeric and homomeric) form pentameric channels, with subunits arranged around a central pore: the homomeric conformation allows for five identical (orthosteric) ACh-binding sites, while the heteromeric conformations allows only two distinct orthosteric sites at each α and β interface (Fig. 2). Muscular nAChRs, like neuronal nAChRs, are pentamers. However; they are made of only five types of subunits (α1, β1, γ1, δ1, and ε1) producing only two receptor types, with an α2βγδ/ε stoichiometry and a (αγαδ/εβ) organization (Albuquerque et al. 2009; Taly et al. 2009; Fasoli and Gotti 2015)).
Acetylcholine (Nicotinic) Receptor, Fig. 2

Heteromeric and homomeric confirmation of nicotinic acetylcholine receptors. Representative diagrams depicting the location of the acetylcholine binding site between α and β subunits in heteromeric (a) and two α subunits in homomeric (b) nAChRs (Adapted from Hopur52009; Accessed 27 July 2016)

Activation, Deactivation, and Desensitization

Despite limitations in the purification and analysis of native human nAChRs, conclusions about the binding of ligands and activation of nAChRs have been drawn, using data obtained from three-dimensional computer modeling and crystallization of ACh-binding proteins (AChBP) from molluscs (reviewed in Dani and Bertrand 2007). The available data suggests that ligands, such as ACh or nicotine, bind to the orthosteric site between the α subunit and the posterior surface of the adjacent subunit. This binding site is predominately composed of the cysteine pair (cys-loop) of the α subunit, which extends around the surface of the neighboring subunit, and is crucial to agonist-induced receptor motion. Binding produces a rotational force in the N-terminal domain, generating torque on M2; to transform it from a hydrophobic closed channel to a hydrophilic channel, favoring ion flow. Other hydrophobic amino acids of the α subunit are required for agonist binding and determine ligand affinity, while residues contributed by the neighboring subunit define ligand selectivity (Albuquerque et al. 2009). In general, nAChR activation in neurons stimulates the opening of a nonselective cation channel, leading to Na+ influx, membrane depolarization, and subsequent activation of voltage-gated Ca2+ channels. This process occurs within milliseconds and is critical for fast synaptic transmission. The estimated permeability of Ca2+ is roughly 0.1 for muscle, 2.0 for heteromeric neuronal assemblies, and ≥10 for homomeric subtypes and heteromeric combinations that include α9 or α10 subunits (Dani and Bertrand 2007). The large increase in calcium influx seen for α7-containing receptors is caused by the combination of charged residues arranged at the mouth of the pore, and polar residues opposite. Removal or substitution of specific residues both within the inner pore of α7 receptors and at the synaptic extracellular end can dramatically decrease or even suppress calcium permeability, illustrating the importance of conserved amino acid sequences within this system (Dani and Bertrand 2007).

Agonist binding at nAChRs produces a transition between four discrete conformations; open, resting, and two closed channel states (I and D), more commonly referred to as states of desensitization (Fig. 3). Both the ligand concentration and the rate of exposure are significant factors in the transition between these states. Equilibrium can be both allosterically regulated, or by traditional ligand binding (reviewed in Changeux and Edelstein 1998). Allosteric modulation occurs at sites distinct from the primary binding site; in high affinity nAChRs by the binding of steroids (specifically 17-β-estradiol) or smaller ligands (such as galantamine and zinc). Allosteric modulators can have both positive and negative effects, with literature referencing examples of allosteric modulators facilitating agonist binding at low concentrations, both increasing and decreasing the energy barrier needed for the receptor to move between open, closed, and desensitized states, and in some cases relatively nonspecific blocking of the ligand binding site or receptor pore (Dani and Bertrand 2007). In the case of α4β2 nAChRs, 17-β-estradiol has been seen to both increase the potency of the orthosteric agonist, as well as increase acetylcholine-evoked currents (Chatzidaki and Millar 2015). With its fast kinetics and unique structure, homomeric α7-containing nAChRs are distinctive targets for allosteric modulation, with specific focus on the alteration of the rate of desensitization. In this regard, most allosteric modulators that target α7 nAChRs are classified as type I, increasing peak current without altering the rate of desensitization, or type II, seen to dramatically reduce the rate of desensitization (Chatzidaki and Millar 2015). Phosphorylation of intracellular domains of some nAChR subtypes provides another form of allosteric modulation (Nakayama et al. 2006) and has been shown to occur frequently for the α7 subtype (Chatzidaki and Millar 2015). Phosphorylation (or dephosphorylation) can directly modify the influence of nAChRs over cell function and also modify nAChRs within the cell membrane. Muscular nAChRs have also shown to be regulated via receptor phosphorylation (Changeux and Edelstein 1998).
Acetylcholine (Nicotinic) Receptor, Fig. 3

Receptor transition from resting to desensitized state. (a) The nAChR is nonconductive in the resting state. (b) Following ligand binding to the nAChR, the receptor transitions to the open state, allowing ion passage. (c) The nAChR transitions to the desensitized state when high levels of or long exposure to ligand occurs. During this state the receptor is closed and does not conduct ions (Image created using Servier; Accessed 27 July 2016)

Transition from an open to resting state (referred to as deactivation) is initiated by dissociation of the agonist from the receptor by reverting to a nonconducting state. nAChRs experience rapid dissociation, and during sustained exposure to a ligand, will experience frequent transitions between the resting and open states (Albuquerque et al. 2009). During high levels or prolonged periods of high-affinity agonist exposure, such as in the case of nicotine exposure, the likelihood of receptor desensitization increases. This is a conformational transition to a highly stable, nonconducting, agonist-bound state. The rate of desensitization, the degree of inhibition caused, and the rate of recovery are dependent on the subunit composition of the receptor, agonist properties of the ligand, and influenced by both kinase and phosphatase activity (Dani and Bertrand 2007). Generally, sustained exposure of a ligand such as ACh to multiple nAChRs will lead to an internalization of unnecessary receptors, commonly known as downregulation. In the case of nicotine however, a distinct part of its mechanism of action results in a global upregulation of functional surface nAChRs. This is thought to be due to either increased synthesis and trafficking of receptors to the cell surface or decreased turnover (Dani and Bertrand 2007).

Subunit Diversity and Localization

While all nAChRs share a common basic structure, their physiological, pharmacological, and pathological properties are defined by their subunit composition and stoichiometric ratio. This imparts an array of modulatory functions within the body, with nAChRs seen to regulate a wide array of processes such as neurotransmitter release, inflammation, cell excitability, and metabolic tone (Reviewed in Dani and Bertrand 2007). From early binding studies, it was determined that the most significant and diffuse receptor subtype in the human brain was the α4β2* formation (where *denotes the inclusion of other possible unidentified receptor subtypes), accounting for 90% of high-affinity nAChRs. Since then various subtype combinations have been located in major central and peripheral pathways throughout the brain (for the distribution of native subtypes in the brain, see Fasoli and Gotti 2015).

The extensive presynaptic, postsynaptic, and nonsynaptic locations of nAChRs underlie their modulatory roles throughout many areas of the brain. The activation of presynaptic nAChRs induces the stimulation of multiple neurotransmitter systems, through direct Ca2+ influx-mediated neurotransmitter release; Ca2+-induced Ca2+ release (CICR) from intracellular stores; and activation of presynaptic voltage-gated Ca2+ channels via neuronal depolarization (Albuquerque et al. 2009). While these are the most abundant and most frequently cited location of nAChRs within the brain, there is also evidence of nAChRs at preterminal sites, where they have been seen to locally depolarize neuronal membranes, and nonsynaptic nAChRs, that may influence the spread of synaptic inputs, neuronal excitation, and the moment-to-moment resting membrane potential due to their axonal, dendritic, and somal locations (Gotti and Clementi 2004). While aptly named as such, there is also a significant amount of evidence to illustrate the expression of a handful of neuronal subtypes (such as α7, α9, and α10) with a highly specialized function in many nonneuronal cell types, namely endothelial cells, keratinocytes, and multiple immune cell types. In the case of muscular nAChRs, the expression is based on the level of muscle innervation, mediating fast and direct synaptic transmission at the neuromuscular junction and ganglia (Gotti and Clementi 2004; Hurst et al. 2013).

While most nAChR subunits form a fairly restricted number of combinations, receptor assembly involving accessory subunits contribute to differences in other significant characteristics of nAChRs such as ion permeability and desensitization. For example, while the α5 subunit alone lacks functionality, coexpression with α4* receptors results in a significant increase in expression and blunts their desensitization in the presence of nicotine. Alterations in nAChR channel kinetics are also observed with the expression of the α5 subunit in α3β4 nAChRs (α3α5β2) with burst duration increasing almost threefold, while colocalization of the α7 subunit can impart changes in ion permeability (Albuquerque et al. 2009). Furthermore, work in Xenopus oocytes by Zwart and Vijverberg in 1998 revealed that different expression ratios evoked altered agonist responses. For α4β2, a 1:1 ratio of subunits available for expression educed the maximal current, while a 1:9 ratio increased ACh sensitivity and reduced desensitization overall. nAChR ligands will also favor certain receptor stoichiometry, with nicotine acting to modulate receptor assembly, favoring the formation of (α4)2(β2)3 (Albuquerque et al. 2009). While the examples of nAChR diversity are endless, it should be noted that the local regulation of receptor assembly and stoichiometry impart significant changes in mature receptor function.

Health Implications

Historically, there are abundant examples of naturally produced, highly subunit selective nAChR toxins. These are used both as deterrents and predatory mechanisms, due to nAChRs central role in regulating both muscular and nervous system functions. The most notable of these is nicotine, produced by tobaco plants as a defense mechanism against predators; and until the 1960s was utilized as a natural insecticide (Pomerleau 1992). The importance of nicotinic receptors and their involvement in healthy development and aging has since been well documented, with their perturbation or dysfunction observed in many disease states ranging from autoimmune disorders, pain, and inflammation through to mental disorders like schizophrenia and Alzheimer’s disease (see Table 1). Below are brief descriptions of some of the disorders which result when the normal function of nAChRs are disrupted (for reviews see Hurst et al. 2013; Schaaf 2014).
Acetylcholine (Nicotinic) Receptor, Table 1

Nicotinic receptor subunits and diseases

Subunit

Pathology

Cholinergic pharmacotherapeutics

Alpha 1

Congenital myasthenic syndrome (slow channel)

Congenital myasthenic syndrome (fast channel)

Lethal multiple pterygium syndrome

Myasthenia gravis

nAChR blockers

Acetylcholinesterase inhibitors

N/A

Acetylcholinesterase inhibitors

Alpha 2

Nocturnal frontal lobe epilepsy, type 4

Nicotine

Alpha 3

Addiction

α3β4 partial agonists, non-selective nAChR antagonists

Alpha 4

Autosomal dominant nocturnal frontal lobe epilepsy, type 1

Alzheimer’s disease

Schizophrenia

Parkinson’s disease

ADHD

Depression

Addiction

Nicotine, α4β2 partial agonists

Acetylcholinesterase inhibitors, α4β2 partial agonists

α4β2 partial agonists

Nicotine, α4β2 partial agonists

α4β2* partial agonists

Non-selective nAChR antagonists

α4β2 partial agonists and antagonist, nonselective nAChR antagonists

Alpha 5

None known

N/A

Alpha 6

Parkinson’s disease

ADHD

Addiction

Nicotine

α6β2* partial agonists

α6 * partial agonists, nonselective nAChR antagonists

Alpha 7

15q13.3 microdeletion syndrome

Alzheimer’s Disease

Schizophrenia

Parkinson’s disease

ADHD

Depression

Addiction (morphine and cannabinoids, not smoking or alcohol)

N/A

Acetylcholinesterase inhibitors, α7 partial and full agonists and antagonists

α7 partial and full agonists and antagonists

Nicotine

α7 agonists

Nonselective nAChR antagonists

α7 antagonists

Alpha 9

None known

N/A

Alpha 10

None known

N/A

Beta 1

Congenital myasthenic syndrome (slow channel)

Congenital myasthenic syndrome (acetylcholine receptor deficiency)

nAChR blockers

Acetylcholinesterase inhibitors

Beta 2

Nocturnal frontal lobe epilepsy, type 3

Alzheimer’s Disease

Schizophrenia

Parkinson’s disease

ADHD

Addiction

Nicotine, α4β2 partial agonists

Acetylcholinesterase inhibitors, α4β2 partial agonists

α4β2 partial agonists

Nicotine, α4β2 partial agonists

α4β2 and α6β2* partial agonists

β2* partial agonists and antagonist, nonselective nAChR antagonists

Beta 3

None known

N/A

Beta 4

None known

N/A

Delta

Congenital myasthenic syndrome (slow channel)

Congenital myasthenic syndrome (fast-channel)

Lethal multiple pterygium syndrome

Myasthenia gravis

nAChR blockers

Acetylcholinesterase inhibitors

N/A

Acetylcholinesterase inhibitors

Epsilon

Congenital myasthenic syndrome (slow channel)

Congenital myasthenic syndrome (fast-channel)

Congenital myasthenic syndrome (acetylcholine receptor deficiency)

Myasthenia gravis

nAChR blockers

Acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors

Gamma

Escobar syndrome

Lethal multiple pterygium syndrome

N/A

N/A

Created using Gotti and Clementi (2004), Albuquerque et al. (2009), Taly et al. (2009), Hurst et al. (2013), and Schaaf (2014)

Myasthenia Gravis

Myasthenia gravis is a chronic autoimmune disorder, characterized by skeletal muscle weakness which increases with physical activity and subsides upon resting. The disorder results from the disruption of signal transmission from the nerves to the muscles at the neuromuscular junction. The body’s own immune system produces antibodies which block, alter, or destroy the nAChRs, preventing the binding of acetylcholine (Schaaf 2014). The disorder is commonly treated with anti-acetylcholinesterases, immunosuppressants, and/or thyroidectomy.

Congenital Myasthenic Syndrome

Similar to myasthenia gravis, congenital myathenic syndrome is characterized by muscle weakness on physical exertion and results from a disruption in signaling at the neuromuscular junction. However, the disorder is caused by a genetic mutation, usually inherited, in one of the components of the cholinergic signaling pathway within the neuromsucular junction. Predominantly the mutations occur in nAChR genes, but they have also been found in the muscle-specific tyrosine kinase and rapsyn genes (Schaaf 2014). Treatment depends on the type of genetic mutation and the proteins it affects. Cholineterase inhibitors have been used for insufficent acetylcholine levels or nAChRs which open for reduced time. Whereas nAChR blockers (like quinidine, fluoxetine) are used for receptors which stay open too long. Ephedrine has been used for mutations which alter postsynaptic signaling.

Multiple Pterygium Syndrome

Multiple pterygium syndrome can be diagnosed before birth due to a lack of muscle movement and skin webbing at the joints. The lack of muscle movement often results in muscle weakness and joint deformities which can prevent the limbs from being fully extended. Typically, the syndrome is inherited and caused by mutations in the CHRNG gene which affect production of the gamma subunit of nAChRs leading to disruptions in signaling at the neuromuscular junction (Schaaf 2014). The syndrome is lethal when no gamma subunits are produced. In the Escobar form, some gamma subunits are produced, with the gamma subunit being replaced by the epsilon subunit shortly after birth, resulting in the restoration of muscle function.

Nocturnal Frontal Lobe Epilepsy

This type of hereditary epilepsy involves brief reoccurring and clustered seizures which arise in the frontal lobe. Generally it is caused by mutations in CHRNA2, CHRNA4, and CHRNB2 genes which disrupts neuronal signal transmission within the brain; however mutations in other non-nAChR genes have been reported (Schaaf 2014).

Alzheimer’s Disease

Alzheimer is a chronic progressive neurodegenerative disease. Its symptoms include dementia, language problems, disorientation, mood swings, loss of motivation, lack of self-care, behavioral issues, and loss of body functions leading to death. It is well known that the accumulation of plaques, development of neurofibrillary tangles, and neuronal loss produce the symptoms of Alzheimer’s disease; however the cause of these neurological changes is still poorly understood. The cholinergic system has been hypothesized to play role in Alzheimer’s disease as both α4 and α7 subunits have been associated with the accumulation of β amyloid protein which results in plaque formation and the hyperphosphorylation of tau leading to the formation of tangles (Hurst et al. 2013). Cognitive deficits have also been reported to improve with the use of nicotine and nAChR agonists. Acetylcholinesterase inhibitors are most commonly prescribed to increase the amount of acetylcholine available for interacting with nAChRs as the loss of cholinergic activity within the cortex and reduction of nAChR expression in the hippocampus are correlated with the severity of symptoms and cognitive decline.

Schizophrenia

A chronic and highly debilitating mental disorder, schizophrenia is characterized by hallucinations, delusions, social withdrawal, and cognitive impairment. While the causes of schizophrenia remain elusive it has been proposed that the disorder primarily results from disruptions in cholinergic signaling between nucleus accumbens and prefrontal cortex (Sarter et al. 2005). This hypothesis has been proposed based on two observations: smoking occurs at a significantly higher rate in schizophrenics compared to the rest of the population (Hurst et al. 2013); and repeated psychostimulant use model aspects of the sensitized activity of ventral striatal dopaminergic transmission that is observed in patients exhibiting psychotic symptoms. More specifically, nicotine interacts with nAChRs and dopaminergic signaling is modulated by nAChRs. Both α4β2 and α7 have been linked to cognitive function and hence are targets for the development of novel treatments and numerous clinical trials (Hurst et al. 2013).

Parkinson’s Disease

Parkinson’s disease results from the degeneration of dopamine neurons within the nigrostriatal pathway of the brain producing a number of motor and nonmotor problems. While the cause of cell death remains elusive, the mechanisms behind the symptoms produced are well understood. The secretion of dopamine from neurons within the nigrostriatal pathway causes a release of inhibition, allowing the activation of neurons which modulate functions like motor activities (Obeso et al. 2008). As mentioned above, nAChRs influence dopamine release and like schizophrenia, smoking has a neuroprotective effect: it both reduces the risk of developing Parkinson’s and slows the progression of symptoms (Taly et al. 2009; Hurst et al. 2013; Schaaf 2014). Both α4β2* and α6* nAChRs have been implicated in the disease. They are the main receptor subtypes responsible for dopamine release in this area of the brain and their expression (along with α7) decreases with disease progression (Hurst et al. 2013; Schaaf 2014).

Attention Deficit Hyperactivity Disorder (ADHD)

ADHD is a neurodevelopmental disorder with unknown cause. It has been proposed that the symptoms are caused by functional deficits in the brains dopaminergic, cholinergic, and noradrenergic pathways which originate in the ventral tegmental area and locus coeruleus and project to the prefrontal cortex and striatum (Sarter et al. 2005; Chandler et al. 2014). Given the role of nAChRs in regulating these brain regions, a number of clinical trials have been undertaken using compounds targeting the α4β2*, α6β2*, and α7 nAChRs (Hurst et al. 2013). The results of these studies are mixed but suggest α4β2* nAChRs are a viable treatment target for adults with ADHD (Hurst et al. 2013).

Addiction

While the neurocircuitry underlying addiction is complex, it is now widely known that neuronal nAChRs play a significant role in the modulation of the mesolimbic dopaminergic pathway within the brain, contributing to the pathology of nicotine and alcohol dependence. Research into addiction, outside of nicotine and alcohol dependence, is still in the early stages, but current evidence supports the role of nAChRs in addiction in general. While multiple nAChR subtypes have been implicated in perpetuating addictive disorders, there is much evidence to support the notion that specifically α4β2 and α3β2 are important therapeutic targets for nicotine addiction, with a combination of nAChR targets noted to be more beneficial for reducing alcohol consumpton. To date, preclinical studies have also focused on nAChR-targeted pharmacotherapeutics in cocaine, methamphetamine, and cannabinoid misuse (Rahman 2013).

Depression and Anxiety

The role of nAChRs in depression is clear: nicotine consumption is higher in individuals with depression, its administration can improve depression in nonsmokers and many commonly prescribed antidepressants are noncompetitive antagonists at nAChRs (Picciotto et al. 2002). The role of nAChRs in anxiety is more complex as nicotine administration has been reported to both increase and reduce anxiety levels in various rodent studies depending upon how the nicotine was administered, the receptor subtypes and neurotransmitter systems involved, and the time course of activation and inactivation of the receptors (Picciotto et al. 2002). Both behaviors are controlled by the dopaminergic and cholinergic pathways within the brain and modulated by nAChRs (Gotti and Clementi 2004). Transgenic mouse studies suggest the α4 and α7 subunits are important in both behaviors (Picciotto et al. 2002). In vitro studies confirm these results and suggest that the α5, α6, β2, and β3 subunits may also be capable of modulating the neurotransmitter pathways which contribute to both anxiety and depression (Picciotto et al. 2002).

Summary

nAChRs belong to a superfamily of ligand-gated ionotropic receptors. They bind to acetylcholine and have a high affinity for nicotine. There are two types of receptors: neuronal nAChR, which are found throughout the central nervous system; and muscular nAChRs, which are located in muscles and neuromuscular junctions. Neuronal nAChRs can take homomeric (α7–9) or heteromeric (α2–6, 10 and β1–4) forms, whereas muscular nAChRs are made of only five types of subunits (α1, β1, γ1, δ1, and ε1). Ligand binding and dissociation mediate their transition between open, resting, and desensitized states, with transition to the open state resulting in activation of voltage-gated Ca2+ channels. The functional properties of nAChRs and the biophysiological changes caused by transitions between these states are dependent upon the subunit composition (assembly and stoichiometry), their location, and the signaling pathways that they influence. Such diversity and widespread dispersion within the body means their perturbation or dysfunction causes many disease states, from autoimmune disorders, pain and inflammation to schizophrenia and Alzheimer’s disease. As a result, nAChRs are largely the focus of novel pharmacotherapeutic research.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Josephine R. Tarren
    • 1
  • Joan Y. Holgate
    • 1
  • Selena E. Bartlett
    • 2
  1. 1.Queensland University of TechnologyBrisbaneAustralia
  2. 2.Queensland University of Technology (QUT)BrisbaneAustralia