Invited reviewDiversity of native nicotinic receptor subtypes in mammalian brain
Introduction
In 1905, Langley (Langley, 1905) reported that nicotine produces short-term stimulation followed by long-term blockade of skeletal muscle, and concluded that it interacted with a receptive substance expressed in skeletal muscle. Langley postulated his theory thirty years before it was demonstrated that acetylcholine (ACh) is present at neuromuscular junctions (Dale et al., 1936), but it was not until the early 1980s that the structure and functions of nicotine-binding receptors (AChR) were discovered.
Nicotine is a highly lipophilic compound present at high level in tobacco leaves which can be smoked, chewed, or sniffed. Once in the bloodstream, nicotine rapidly crosses the blood–brain barrier and accumulates in the brain (Hukkanen et al., 2005), where it binds with high affinity the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs in the brain represent a heterogeneous family of ubiquitously expressed pentameric ion channels, whose responses to endogenous neurotransmitter ACh and exogenous nicotine are involved in a number of physiological processes and pharmacological effects (Albuquerque et al., 2009, Dani and Bertrand, 2007, Hurst et al., 2013).
nAChR activation excites target cells and mediates fast synaptic transmission in autonomous ganglionic neurons and in some brain areas. Anatomical and functional evidence suggests that most of these receptors have a presynaptic and/or preterminal localisation, and modulates the release of almost all neurotransmitters, but some also have a somatodendritic post-synaptic localisation (Albuquerque et al., 2009, Gu and Yakel, 2011). In brain, the nAChRs regulate the release of both excitatory and inhibitory neurotransmitters, as a consequence, the activation of nAChRs can have opposite modulatory effects on the same circuit depending on whether they are expressed on excitatory or inhibitory neurons (Jensen et al., 2005, Albuquerque et al., 2009).
nAChRs and nicotinic mechanisms contribute to cognitive function and their decline or dysfunction has been observed in several neuropsychiatric diseases (Lewis and Picciotto, 2013, Higley and Picciotto, 2014). In addition, genetic studies have linked nAChRs to epilepsy and schizophrenia, and studies of mutant (knock-out, Ko, or knock-in, Kin) mice have shown that they are involved in pain mechanisms, anxiety depression and nicotine addiction (Picciotto et al., 2001, Champtiaux and Changeux, 2002, Gotti and Clementi, 2004, Changeux, 2010b, Drenan and Lester, 2012, Hurst et al., 2013).
Nicotine binding activates nAChRs, but bound nAChRs can also be desensitised and inactivated by nicotine sometimes regardless of nAChR activation (reviewed in Picciotto, 2003). Moreover chronic nicotine exposure leads to neural adaptations that may be due to nAChR activation and/or desensitisation and, in the latter case, nicotine can alter neuronal function by interrupting the transmission of endogenous neurotransmitter ACh (Changeux, 2010a, Colombo et al., 2013).
The advent of new technologies such as optogenetics, the generation of mice carrying deletions or the expression of gain-of-function nAChR subunits and the use of lentiviral vectors to re-express nAChR subunits in selected brain regions of Ko mice or specific receptor subtype genes, tagged with GFP (Drenan and Lester, 2012, Fowler and Kenny, 2012) has greatly increased our understanding of the functional role of specific receptor subtypes in nervous system physiology and pathology.
As a number of comprehensive reviews have described the structure and function of nAChRs (Picciotto et al., 2001, Gotti and Clementi, 2004, Albuquerque et al., 2009, Jensen et al., 2005, Dani and Bertrand, 2007, Changeux, 2010a, Hurst et al., 2013).
The aim of this article is to provide a short overview of some recent aspects of the structure and function of nAChR subtypes, particularly those present in the habenulo-interpeduncular (Hb-IPN) pathway and to compare the expression of nAChR subtypes in rodents and primate brains.
Section snippets
Structure of nicotinic receptor subtypes
Studies using numerous complementary approaches have made it possible to define the structure function and pharmacology of nAChRs. Ligand binding assays have been used to identify and characterise brain nAChRs for more than 40 years (Patrick and Stallcup, 1977) and radioactive ligand have shown that 125I-αBungarotoxin (αBgtx) and 3H-nicotine bind to receptors that have different anatomical and pharmacological distributions (Clarke et al., 1985).
The pharmacological heterogeneity of nAChRs
Native nAChR subtypes
The approaches currently used to localise and identify nAChR subtypes include techniques for localising subunit mRNA (in situ hybridisation (ISH) and single-cell PCR) or protein (immunoprecipitation and immunocytochemistry), receptor autoradiography at regional or cellular level, techniques for assessing subtype composition and pharmacology (binding in tissue homogenates, immunoprecipitation, immunopurification and Western blotting) and functional assays (neurotransmitter release from slices or
Acknowledgements
Due to space constraints we have been unable to cite all original papers and we apologise to authors whose work in this area has been omitted.
This work was supported by the CNR Research Project on Aging, Regione Lombardia Projects NUTEC ID 30263049 and MbMM-convenzione n° 18099/RCC (CG), and by grant from the Italian Ministry of Health RF2009-1549619 (MZ).
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