Elsevier

Progress in Neurobiology

Volume 74, Issue 6, December 2004, Pages 363-396
Progress in Neurobiology

Neuronal nicotinic receptors: from structure to pathology

https://doi.org/10.1016/j.pneurobio.2004.09.006Get rights and content

Abstract

Neuronal nicotinic receptors (NAChRs) form a heterogeneous family of ion channels that are differently expressed in many regions of the central nervous system (CNS) and peripheral nervous system. These different receptor subtypes, which have characteristic pharmacological and biophysical properties, have a pentameric structure consisting of the homomeric or heteromeric combination of 12 different subunits (α2–α10, β2–β4).

By responding to the endogenous neurotransmitter acetylcholine, NAChRs contribute to a wide range of brain activities and influence a number of physiological functions. Furthermore, it is becoming evident that the perturbation of cholinergic nicotinic neurotransmission can lead to various diseases involving nAChR dysfunction during development, adulthood and ageing. In recent years, it has been discovered that NAChRs are present in a number of non-neuronal cells where they play a significant functional role and are the pathogenetic targets in several diseases. NAChRs are also the target of natural ligands and toxins including nicotine (Nic), the most widespread drug of abuse.

This review will attempt to survey the major achievements reached in the study of the structure and function of NAChRs by examining their regional and cellular localisation and the molecular basis of their functional diversity mainly in pharmacological and biochemical terms. The recent availability of mice with the genetic ablation of single or double nicotinic subunits or point mutations have shed light on the role of nAChRs in major physiological functions, and we will here discuss recent data relating to their behavioural phenotypes. Finally, the role of NAChRs in disease will be considered in some details.

Introduction

The cholinergic system is one of the most important and filogenetically oldest nervous pathways. Acetylcholine (ACh) is the neurotransmitter that is synthesised, stored and released by cholinergic neurons, and the key molecules that transduce the ACh message are the cholinergic muscarinic and neuronal nicotinic acetylcholine receptors (NAChRs). NAChRs are widely expressed in the nervous system, where they transduce cholinergic transmission at the synapses in the peripheral ganglia and in various brain areas. In the central nervous system (CNS), the cholinergic innervation acting via NAChRs regulates processes such as transmitter release, cell excitability and neuronal integration, which are crucial for network operations and influence physiological functions such us arousal, sleep, fatigue, anxiety, the central processing of pain, food intake and a number of cognitive functions (Changeux and Edelstein, 2001, Gotti et al., 1997a, Hogg et al., 2003, Lindstrom, 1997, McGehee and Role, 1995, Role and Berg, 1996). Furthermore, it is becoming evident that the perturbation of cholinergic nicotinic neurotransmission can lead to various diseases involving NAChR dysfunction during development, adulthood and aging (Changeux and Edelstein, 2001, Gotti et al., 1997a, Hogg et al., 2003, Lindstrom, 1997).

This review will attempt to survey the major achievements reached in the study of the structure and function of NAChRs by examining their regional localisation and the molecular basis of their functional diversity mainly in pharmacological and biochemical terms. The recent availability of mice with the genetic ablation of single or double nicotinic subunits (knock out, Ko) or a single gene mutation (knock in, Kin), have shed light on the role of NAChRs in major physiological functions and we will here discuss recent data relating to their phenotypes. We will draw the attention of the reader on the relatively new discovery of NAChRs in non-neuronal cells and we will discuss their relevance in physiology and pathology of the tissues where they are present. Finally, the role of nAChRs in pathology will also be considered. For the specific aspects of nAChR physiology, cell biology, pharmacology and pathology that are not covered by this review, we would like to draw the attention of readers to various excellent reviews (Arneric and Holladay, 2000, Changeux and Edelstein, 2001, Corringer et al., 2000, Dajas-Bailador and Wonnacott, 2004, Decker et al., 2004, Dwoskin and Crooks, 2001, Hogg et al., 2003, Lester et al., 2003, Picciotto, 2003, Picciotto et al., 2001).

NAChRs are a family of cationic channels consisting of different subtypes, each of which has a specific pharmacology, physiology and anatomical distribution in brain and ganglia. They belong to the gene superfamily of ligand-gated ion channels (of which muscle AChRs are the prototype), which also includes gamma aminobutyric acid (GABAA and GABAC), glycine and 5-hydroxytryptamine (5-HT3) receptors (reviewed in Changeux and Edelstein, 1998, Karlin, 2002, Le Novere and Changeux, 1995).

Earlier studies designed to characterise NAChRs were based on binding assays with nicotinic radioligands in different brain areas reviewed in (Lukas and Bencherif, 1992). These demonstrated that at least two distinct classes of putative NAChRs exist in the nervous system: one consisting of receptor molecules that bind 3H-agonists with nM affinity but not αBungarotoxin (αBgtx) (from now on called nAChRs), and the other that bind the agonists with μM affinity and αBgtx with nM affinity (from now on called αBgtx-nAChRs).

The pharmacological heterogeneity of NAChRs revealed by these ligand studies was later confirmed and extended by means of the molecular cloning of a family of genes encoding various subunits. Twelve genes coding for NAChR subunits have so far been cloned and, like all of the other members of the ligand-gated ion channel superfamily, they encode for peptides that all have a relatively hydrophilic extracellular amino terminal portion, followed by three hydrophobic transmembrane domains (M1–M3), a large intracellular loop, and then a fourth hydrophobic transmembrane domain (M4) (reviewed in Hogg et al. (2003); Sargent (1993)). These subunits have a common ancestor, have been highly conserved during evolution, and the same subunit has more than 80% amino acid identity across vertebrate species Fig. 1A (Le Novere and Changeux, 1995).

The genes that have been cloned so far are divided into two subfamilies of nine neuronal α subunits (α2–α10) and three β subunits (β2–β4) (Le Novere and Changeux, 1995, Lindstrom, 2000). The α subunits have two adjacent cysteines that are homologous to those present at positions 192 and 193 of the α1 subunit of muscle-type AChRs whereas the β subunits (β1–β4) lack the pair of adjacent cysteines (reviewed in Le Novere and Changeux, 1995, Changeux and Edelstein, 1998). Both α and β subunits contribute towards the pharmacological specificity of NAChR subtypes (Luetje and Patrick, 1991).

On the basis of their different phylogenetic, functional and pharmacological properties, the heterogeneous family of NAChR subtypes have been divided into two main classes: the αBgtx-nAChRs, which may be homomeric (made up of α7–α9 subunit homo-pentamers) or heteromeric (made up of α7, α8 or α9, α10 subunit hetero-pentamers), and the nAChRs, which contain the α2–α6 and β2–β4 subunits, and only form heteromeric receptors that bind agonists with high affinity (reviewed in Lindstrom, 2000).

It is presumed that both homomeric and heteromeric nAChRs have a pentameric structure with the subunits organised around a central channel: the homo-oligomeric receptors have five identical ACh-binding sites per receptor molecule (one on each subunit) located at the interface between two adjacent subunits, whereas the hetero-oligomeric receptors have two α subunits and three β subunits and therefore two binding sites per receptor molecule located at the interface between the α and β subunits see (Fig. 1B and C). The ACh binding site has a principal and a complementary component. In heteromeric nAChRs, the principal component is carried by the α2–α4 and α6 subunits with the complementary site carried by the β2 or β4 subunits, whereas each subunit in the homomeric receptors contributes to both the principal and complementary components of the binding site (Changeux and Edelstein, 1998, Corringer et al., 2000) (see Fig. 1C). Notwithstanding their initial classification in the α and β subunit list, respectively, α5 and β3 subunits carry neither the principal nor the complementary component of ACh binding site and are therefore considered auxiliary subunits (see below).

A significant contribution to the identification of the ligand binding site in NAChRs was made by the crystal structure of the acetylcholine binding protein from the fresh water snail Lymnaea stagnalis. This homopentameric soluble protein is 210 residues long, binds ACh, is secreted by snail glial cells into cholinergic synapses (Brejc et al., 2001, Smit et al., 2001) and is analogous to the extracellular ligand binding domain of the NAChRs. Structural data of the crystallised acetylcholine binding protein have revealed that the topology of the binding sites is very similar to that predicted by mutations and computer modelling.

Functionally, the different NAChR subtypes can exist in four distinct conformations: resting, open, and two ‘desensitised’ closed channel states (I or D) that are refractory to activation on a timescale of milliseconds (I) or minutes (D), but have a high affinity (pM–nM) for agonists. The binding of ligands to the receptors at the neurotransmitter binding site or in any of the allosteric sites can modify the equilibrium between the different conformational states of the receptors. Moreover, the transition between the different receptor states can also be regulated by receptor phosphorylation, as has been shown in the case of muscle-type receptors (reviewed in Changeux and Edelstein, 1998).

In heterologous systems, the expression of the α7–α9 subunits alone produces homomeric receptor channels activated by ACh and blocked by nanomolar concentrations of αBgtx with high Ca2+ permeability and a rapid desensitisation rate. The α7-containing subtypes account for most of the high affinity αBgtx binding sites in the central and peripheral nervous systems of different species. The α8-containing receptors are only present in the chick nervous system, where they not only form homomeric receptors, but also heteromeric α7–α8 receptors (Gotti et al., 1994, Keyser et al., 1993). The α9-containing receptors are expressed extraneuronally and have an unusually mixed nicotinic-muscarinic pharmacological profile (Elgoyhen et al., 1994). α7-Containing receptors have been found in many brain regions and are especially concentrated in the hippocampus, where they can presynaptically facilitate the release of transmitters such as glutamate or GABA (Alkondon et al., 1996, MacDermott et al., 1999), or exert a direct postsynaptic action by mediating fast synaptic transmission (Jones et al., 1999, MacDermott et al., 1999). The α7-containing receptors are also found in perisynaptic locations, where they modulate other inputs to neurons and activate a variety of downstream signalling pathways (Berg and Conroy, 2002, Shoop et al., 1999). The α7-containing receptors on autonomic ganglia are involved in fast synaptic transmission despite their perisynaptic localisation (Dajas-Bailador and Wonnacott, 2004, MacDermott et al., 1999).

The α10 subunit is similar to the α9 subunit by amino acid sequence (Elgoyhen et al., 2001, Sgard et al., 2002), but oocyte injections of the mRNA encoding the α10 subunit alone or in combination with mRNA encoding for the α2–α6 subunits or β2–β4 subunits give no detectable currents. A new current that is distinct from that of the homomeric α9 receptors was detected only when mRNAs coding for the α9 and α10 subunits were coinjected. This new current has functional and pharmacological properties that are indistinguishable from those of the endogeneous cholinergic receptors present in cochlear hair cells, which have transcripts for both the α9 and α10 subunit genes (Elgoyhen et al., 2001, Sgard et al., 2002).

Recent studies have shown that the α7 subunit can also form functional channels with the subunits of nAChRs. This has been shown in oocytes in which a mutated form of the chick α7 subunit (L247Tα7) co-assembles with the β3 subunit (Palma et al., 1999), and a rat α7 subunit co-assembles with the β2 subunit when expressed in heterologous systems (Khiroug et al., 2002). Heteromeric L247Tα7β3 receptors have less ACh affinity and a faster desensitisation rate than L247Tα7 receptors, whereas the heteromeric α7β2 receptors form channels with higher ACh affinity, a slower desensitisation rate, and pharmacological properties that are different from those of the α7 homomeric channel (Khiroug et al., 2002, Palma et al., 1999).

No biochemical evidence of the presence of α7 heteromeric receptors in vivo is yet available, but multiple functional α7-containing subtypes (some of which have a slower desensitisation rate and reversibly bind αBgtx) have been described in rat hippocampal interneurons, the intracardiac ganglion, the superior cervical ganglion (SCG) and chick sympathetic neurons (Alkondon et al., 1997, Cuevas and Berg, 1998, Cuevas et al., 2000, Yu and Role, 1998b) thus suggesting that these tissues may contain heteromeric α7 receptors or alternatively transcribed α7 subunit.

Studies of native α7 receptors have confirmed that they are as highly permeable to calcium as NMDA receptors but, unlike the latter, do not require depolarisation of the plasma membrane to promote calcium influx. It is likely that the high degree of Ca2+ permeability underlies most of their functions: Ca2+ influx can facilitate transmitter release when presynaptic α7 receptors are activated, depolarises post-synaptic cells and acts as a second messenger to initiate many cell processes, including those promoting neuronal survival (Messi et al., 1997, Role and Berg, 1996). The effects of the Ca2+ entering through α7 receptors are limited by a rapid receptor desensitisation, that prevents the excitotoxicity of an excessive influx, which is mainly due to a 247 leucine residue located in the second transmembrane region. The substitution of the leucine residue responsible for desensitisation with threonine greatly changes the functional and pharmacological properties of the α7 subtype (L247T), leading to a receptor with higher ACh affinity, a reduced desensitisation rate, and no ionic current rectification (Revah et al., 1991). α7 receptor functions are also modulated by divalent cations (including Ca2+ Zn2+, Mg2+, Pb2+, Cd2+) interacting with a site located in the 160–174 region at the N terminal of the α7 subunit of homomeric receptors, potentiates the ACh-induced response (Hogg et al., 2003, McGehee and Role, 1995), and extracellular Ca2+ modulates both the activation and deactivation of α7 receptors in cultured hippocampal neurons (Bonfante-Cabarcas et al., 1996).

Although the functional and pharmacological properties of the subtypes expressed in heterologous systems may be influenced by the type of cells in which they are expressed (Lewis et al., 1997) much of our knowledge concerning the electrophysiological and pharmacological properties of nAChR subtypes comes from these systems. Various functional nAChR subtypes can be generated by injecting neuronal mRNAs or cDNAs encoding α2–α4 or α6 subunits in pairwise combinations with β2 or β4 subunits. These different subtypes (i.e. α2β2, α3β2, α4β2, α6β2, α2β4, α3β4, α4β4 and α6β4) have different biophysical and pharmacological properties, some of which may match those of native nAChRs (Gotti et al., 1997a). Both the α and β subunits determine the pharmacological and functional properties of the expressed subtype: when expressed with the β2 subunit the α2–α4 and α6 subunits all form channels that vary in their average open times, single channel conductance, agonist and antagonist sensitivity. β Subunits appear to regulate the rate at which agonists and antagonists bind and dissociate from the subtypes, and the pharmacological sensitivity of nAChRs (Papke, 1993).

NAChRs are pentamers, but the stoichiometry of many nAChRs remains to be fully elucidated. Biochemical and electrophysiological approaches have shown that both chick α4β2 (Anand et al., 1991, Cooper et al., 1991) and human α3β4 subtypes (Boorman et al., 2000) have a stoichiometry of 2α and 3β when expressed in oocytes injected with cRNAs or cDNAs in a ratio of 1/1 (α/β). However, more recent studies have shown that different classes of functional α4β2 subtypes are formed in oocytes when the rat α4/β2 subunit ratio is varied. When the ratio of α4/β2 is 1:9, the subtypes generated are more sensitive to activation and desensitise more slowly but, when the ratio is 1:1 or 9:1, the α4β2 subtypes are less sensitive to activation and desensitise more rapidly (Zwart and Vijverberg, 1998).

HEK cells stably transfected with the α4β2 subtype have a large majority of receptors with low ACh affinity and slow desensitisation but, when the cells are transiently transfected with the β2 subunit, exposed overnight to nicotine (Nic) or kept at a low temperature (29 °C), there is an increase in the number of receptors that are more sensitive to activation (Nelson et al., 2003). Metabolic labelling of these cells with 35S methionine has shown that the receptors have a stoichiometry of (α4)3 and (β2)2, but long-term exposure to Nic or to low temperature increases the number of receptors with a high affinity for Nic and with a stoichiometry of (α4)2 and (β2)3.

The results of all these studies clearly indicate that the stoichiometry of heterologous subtypes is not only dictated by their cDNA, but also by their relative ratio and possible pharmacological treatments. However, it is not yet known whether this plasticity also exists in neurons in vivo and plays a role in mammalian brain, or whether more stringent rules govern the assembly of the subtypes in native neurons.

A further complexity of the structure of nAChRs is demonstrated by the subtypes containing the α5 and β3 subunits. Neither the α5 nor the β3 subunits can form functional channels when co-expressed with another α or β subunit, which is why they were long referred to as “orphan subunits”. They only form functional channels when are co-expressed with both α and β subunits (Lindstrom, 2000). The chick α5 subunit forms a functional α4β2α5 subtype when co-expressed with the α4 and β2 subunits, and this subtype (in which the α5 subunit participates directly in the lining of the channel) has properties distinct from those of the α4β2 subtype, with a higher Nic-gated conductance, open probability desensitisation rate and Ca2+ permeability, and a higher half-maximal effector concentration (EC50) for nicotinic agonists (Ramirez-Latorre et al., 1996). When expressed with the α3 and β2 subunits, α5 increases sensitivity to ACh, but this effect is not seen when the β2 subunit is replaced by β4 (Wang et al., 1996). Conversely, the presence of the α5 subunit increases Ca2+ permeability and the rate of desensitisation in both α3β2 and α3β4 subtypes. In chick sympathetic neurons, the deletion of the α5 subunit alters the sensitivity of native receptors to both agonist and antagonists (Yu and Role, 1998a).

When co-expressed with the human α3 and β4 subunits, a mutated form of the human β3 subunit (β3V273T) forms functional channels in oocytes whose pharmacological and biophysical properties are different from those of the α3β4 combination (Groot-Kormelink et al., 1998). These receptors have a subunit stoichiometry of 2(α3), 2(β4), and 1(β3) when the injected cRNA have a ratio of 1:1:20.

All these studies together indicate that both the α5 and β3 subunits (known as auxiliary subunits) do not directly participate in the formation of the ligand binding site at the interface of α and β subunits, and may occupy a position comparable to that of the muscle β1 subunit in assembled receptors. They may have a role in controlling ion permeability and perhaps receptor localization.

NAChR expression studies have also demonstrated that both heteromeric and homomeric receptors have two important properties: (a) they are not only permeable to monovalent cations but also to Ca2+; and (b) they are functionally modulated by changes in extracellular Ca2+ regardless of any increase in intracellular Ca2+. In neurons, NAChRs activation can play a relevant role in Ca2+ homeostasis and signalling not only because of the Ca2+ entry through different NAChR subtypes, but also because NAChR depolarisation of the plasma membrane can activate voltage operated calcium channels (VOCCs) and increase intracellular Ca2+, and this may induce Ca2+ mobilisation from intracellular stores. The absolute quantity and strategic localisation of Ca2+ entry through NAChRs is likely to be relevant for the regulation of calcium-mediated events such as transmitter release, cell excitability, gene expression, cell differentiation and survival (reviewed in Bonfante-Cabarcas et al., 1996, Dajas-Bailador and Wonnacott, 2004, McGehee and Role, 1995). The quantity of Ca2+ in the different neuron microdomains depends on the receptor subtypes and their Ca2+ permeability that varies and changes depending on the different subunit combinations. The Ca2+:Na+ permeability ratio of the heteromeric subtypes obtained using different α/β combinations is in the range of 0.1:1.6, but close to 10:20 for the homomeric α7 or α9 receptors (Fucile et al., 2003).

Moreover, a recent technique relying on the simultaneous recording of fluorescent Ca2+ signals and transmembrane currents has given a more direct estimate of the Ca2+ current (in this case referred to as fractional current, Pf) through NAChRs. These studies have confirmed that homomeric α7 receptors have a higher Ca2+ current (a Pf of 6–12% depending on the species) than nAChRs (Pf of 2–5%) (Fucile et al., 2003). This technique has also confirmed that the incorporation of additional subunits in heteromeric receptors can change Ca2+ permeability, as in the case of the α5 subunit in the α3β4 subtype, whose presence greatly increases the calcium permeability of the subtype (reviewed in Fucile et al. (2003)).

Section snippets

Brain cholinergic system

In order to clarify the functions of NAChRs especially in brain, it is useful to summarise the most important cholinergic pathways in which NAChRs act as transducer molecules. The brain cholinergic system is made up of a series of closely connected subsystems consisting of eight major and largely overlapping groups of cells, with the dendrites of one cell contacting those of many others; furthermore, gap junctions and dendrodendritic synapses are relatively common. However, each cell innervates

Changes during development and aging

NAChRs change considerably during development and aging in all animal species. The earliest detection of nAChRs, as mRNA or as ligand binding, is on E7 in chick (Vailati et al., 2003), E11 in rat (Zoli, 2000a, Zoli, 2000b) and after 5–7 weeks of gestational age in human brain (Zoli, 2000b). Studies of 3H-Nic and 125I-αBgtx binding sites and mRNA expression for the individual subunits during development have shown that they have different temporal and spatial behaviours.

Non-neuronal localisations of NAChRs

ACh is probably the oldest signalling molecule, and appeared very early in evolution before nervous cells. It is present in bacteria, algae, protozoa and plants, and so it is not surprising that it is still involved in cell-to-cell communications in various non-neuronal tissues and controls important cell functions such as proliferation, adhesion, migration, secretion, survival and apoptosis in an autocrinal, justacrinal and paracrinal manner (Grando et al., 1993, Sastry et al., 1979). Many of

Studies of knock out and knock in mice

The use of genetically engineered Ko or Kin in which one or more genes of interest are silenced or mutated provides a unique opportunity to analyse the pharmacology and functional role of NAChRs in complex neurobiological systems.

The use of Ko mice may have some drawbacks because their lack of the subunit of interest may lead to some forms of adaptation during development, with the up- or down-regulation of some receptor subtypes that may confound the interpretation of behavioural changes. Only

NAChRs in pathology

Neuronal NAChRs are involved in a wide variety of diseases affecting the nervous system and non-neuronal tissues. We here review the diseases in which NAChR involvement has been experimentally validated.

Conclusions and perspectives

Over the last few years, a number of important technological advances have increased our understanding of the functioning of NAChRs. In particular, the application of new molecular and cellular techniques, immunological assays with subunit-specific Abs for NAChR localisation and purification, in vivo localisation using non-invasive imaging techniques, new selective ligands, and especially the availability of Ko and Kin animals for the individual subunits, have made it possible to correlate the

Acknowledgements

We are grateful to Drs. Jenny Court and Elaine Perry for providing Table 2, Table 3. This work was supported in part by grants from the Italian MIUR (MM05152538) to Francesco Clementi; from the European Research Training Network HPRN-CT-2002-00258, the FISR-CNR Neurobiotecnologia 2003, the Fondazione Cariplo grant no. 2002/2010 to F. Clementi; and from the FIRB (RBNE01RHZM) 2003 to Cecilia Gotti.

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