ReviewStructural and functional diversity of native brain neuronal nicotinic receptors
Graphical abstract
Introduction
Nicotine is a major component of tobacco smoke whose behavioural effects are due to its interactions with a family of acetylcholine (ACh)-gated channels (nicotinic ACh receptors, nAChRs) present in the central and peripheral nervous systems [1], [2], [3], [4], [5]. These share a common basic structure but have specific pharmacological and functional properties that are due to the very different subunit combinations that make distinctive subtypes. nAChRs are not only permeable to monovalent Na+ and K+ ions, but also to Ca2+ ions, and their ability to alter intracellular [Ca2+] [6] by activating different downstream intracellular pathways plays a pivotal role in neuron signalling (reviewed in [7]).
Brain nAChRs have a very widespread and non-uniform distribution. The majority have a presynaptic and/or preterminal localisation where they modulate the release of almost all neurotransmitters, but some also have a somatodendritic post-synaptic localisation [3], [4]. The activation of nAChRs can have opposite modulatory effects in the same circuit depending on where they are expressed (for instance on excitatory or inhibitory neurons) [3], [8]. nAChRs are involved in a wide range of physiological functions in the central and peripheral nervous system, and changes in their number and/or function are associated with a number of pathophysiological conditions.
The recent development of genetically engineered mice with the targeted deletion of specific subunits (knock-out mice, Ko) or mutations in critical receptor domains (knock-in mice, Kin), as well as Ko mice made to re-express nAChR subunits in selected brain regions by means of lentiviral vectors, has led to the in vivo identification of complex subtypes and allowed the study of individual subtypes in specific cells and complex neurobiological systems (reviewed in [1], [9], [10], [11], [12]).
As a number of comprehensive reviews have described the structure and function of nAChRs [3], [4], [5], [13], [14], the aim of this article is to provide a short overview of some aspects that have been the object of recent studies: the composition and function of native nAChR subtypes, particularly those present in the mesostriatal and habenulo-interpeduncular pathways, and how they are modulated by chronic exposure to nicotine.
Section snippets
Structure of the nAChR
nAChRs form a heterogeneous family of subtypes consisting of five subunits arranged around a central pore whose variety is mainly due to the diversity of the possible combinations of the known nine α (α2–α10) and three β (β2–β4) subunits [15]. Unlike the β subunits, all nine α subunits have adjacent cysteines, analogous to cysteines 192–193 of the α subunit of muscle-type nAChRs [16]. The subunits have been cloned from neuron-like cells or cDNA libraries obtained from vertebrate brain, but it
Role of non-ligand-binding (accessory) subunits in pentameric receptors
In heteromeric αBgtx-insensitive receptors, the accessory subunits are those that do not directly participate in forming the binding site. Heterologous expression studies have shown that the α5 and β3 subunits only form functional channels when they are co-expressed with a principal and a complementary subunit [34], [35], thus indicating that they can only function as accessory subunits, whereas the α3 or α4 and β2 or β4 subunits can form ligand binding sites or assemble in the accessory
Subunit stoichiometry
As nAChRs are pentameric, they can show considerable molecular diversity. In addition to the differences in subunit composition, some receptor subtypes may have the same subunit composition but different subunit stoichiometries.
Two different methodological approaches have shown that heterologously expressed α4β2 subtypes have an (α4)2(β2)3 stoichiometry that is highly sensitive to activation by ACh [44], [45]. Subsequently it has been found that the α4β2 subtype has biphasic ACh
nAChR subtype assembly
Expression studies using heterologous systems have shown that nAChR assembly is a tightly regulated and ordered process, which requires appropriate subunit–subunit interactions and perhaps other proteins (chaperones) that can assist receptor assembly [52], [53]. Vertebrate nAChR subunits may co-assemble in many possible combinations, and many more subtypes have been heterologously expressed than those identified in vivo. It seems that native nAChRs are assembled into functional pentamers with a
Native nAChR subtypes
Important contributions to the identification of native nAChRs in the brains of rats and wild-type, Ko and Kin mice have been made using biochemical, immunoprecipitation and immunopurification techniques. It is now well established that the most abundant nAChR subtypes in the nervous system are homomeric α7 receptors and heteromeric receptors containing only one type of α and one type of β subunit [2], [4]. The α4β2* receptors account for 90% of the high affinity neuronal nAChRs in mammalian
Regulation of native subtypes by chronic nicotine exposure
Chronic nicotine exposure gives rise to neural adaptations that change whole cell physiology and behaviour, mainly due to its interaction with nAChRs.
The effects of nicotine may be due to nAChR activation or desensitisation because, also in the latter case, nicotine can alter neuronal function by interrupting the transmission of endogenous ACh [30], [97]. As nAChR subtypes are not equally responsive to nicotine activation and desensitisation, this can influence their functional and behavioural
Conclusions
The fine molecular structure of nAChRs has been better clarified over recent years mainly as a result of very different methodological approaches.
It has been shown that there is a substantial number of native subtypes, although native nAChRs are assembled into functional pentamers made up of a relatively restricted number of subunit combinations. Moreover, the in vivo characterisation of new and unsuspected subtypes (heteromeric α7β2) has increased the complexity of studying native subtypes.
Acknowledgements
The paper was supported by Italian PRIN grant 20072BTSR2 to FC and MZ, and EC Neurocypres grant no. 202088 to CG and MZ, and grants from Fondazione Cariplo (2006/0779/109251) and Compagnia San Paolo (2005-1964) to CG.
Our special thanks go to Dr. Annalisa Gaimarri for drawing the figures.
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