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Gotti C, Clementi FNeuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74:363-396

CNR, Institute of Neuroscience, Cellular and Molecular Pharmacology Section, Department of Medical Pharmacology and Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy.
Progress in Neurobiology (Impact Factor: 10.3). 01/2005; 74(6):363-96. DOI: 10.1016/j.pneurobio.2004.09.006
Source: PubMed

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 (alpha2-alpha10, beta2-beta4). 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.

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    • "The binding site for neurotransmitter or other agonist ligand exists on the interface of the N-terminal domains of two adjacent subunits [18] [20]. Amino acid mutations located in 6 loops (loop A–C from ␣ subunit and loop D–F from ␤ subunit) which constitute the binding pocket have been reported to associate with resistance to neonicotinoids in various insect species [21] [22]. For example, mutations in these loops of insect ␣ subunits and ␤ subunits were reported to be involved in neonicotinoid resistance insecticides in Myzus persicae, Aphis gossypii, N. lugens and Drosophila melanogaster [23] [24] [25] [26] [27] [28]. "
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    ABSTRACT: High sensitivity to neonicotinoid insecticides have been reported in the miridbug Cyrtorhinus lividipennis, an important predatory enemy of rice Planthoppers, such as Nilaparvata lugens (brown planthopper). In the present study, the sensitivity of neonicotinoid insecticides between C. lividipennis and N. lugens were detected and compared. The results showed that neonicotinoid insecticides were much more toxic to the miridbug than to the brown planthopper. A nicotinic acetylcholine receptor subunit was cloned from the miridbug and denoted as α8 subunit (Clα8) according to sequence similarities and important functional motifs. Key amino acid differences were found in specific loops from α8 subunits between C. lividipennis (Clα8) and N. lugens (Nlα8). In order to understand the roles of key amino acid differences in insecticide sensitivities, the different amino acid residues in specific loops of Nlα8 were introduced into the corresponding sites in Clα8 to construct several subunit mutants. Clα8 or subunit mutants were co-expressed with rat β2 to obtain the functional receptors in Xenopus oocytes. The single mutation N191F in loop B reduced imidacloprid sensitivity, with EC50 value in Clα8(N191F)/β2 of 15.21μM and 5.74μM in Clα8/β2. Interestingly, although the single mutation E240T in loop C did not cause the significant change in imidacloprid sensitivity, it could enhance the effects of N191F and cause more decrease in imidacloprid sensitivity. The results indicated that E240T might contribute to neonicotinoid sensitivity in an indirect way. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Neuroscience Letters 01/2015; 589. DOI:10.1016/j.neulet.2015.01.046 · 2.06 Impact Factor
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    • "In recent year, a4b2 and a7 nAChR subtypes are also expressed in immune cells including macrophages, which are involved in the initiation, maintenance and resolution of neuroinflammation (Gotti & Clementi 2004, Kiguchi et al. 2012b). These immune cells may participate in neuropathic pain, and the activation of nAChRs in these immune cells negatively regulates the expression of proinflammatory mediators, such as inter- leukin-1b (IL-1b) (Tracey 2002, Blanchet et al. 2004, de Jonge et al. 2005). "
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    ABSTRACT: AimNeuropathic pain is often refractory to conventional analgesics including opioids and non-steroidal anti-inflammatory drugs. Evidence suggests nicotinic acetylcholine receptor ligands regulate pain transmission. Effects of 42 nicotinic acetylcholine receptor activation on pain behaviours after nerve injury were studied. Methods Mice were subjected to partial sciatic nerve ligation (PSL). Nicotinic acetylcholine receptor 4 and 2 subunits localization in injured nerves were evaluated by immunohistochemistry. Neuropathic pain, assessed by tactile allodynia and thermal hyperalgesia, was examined by von Frey test and Hargreaves test respectively. ResultsNicotinic acetylcholine receptor 4 and 2 subunits were up-regulated in injured nerves and were expressed on F4/80-positive macrophages. When nicotine was perineurally administered daily for 4days (day 7-10; maintenance phase) after nerve injury, pain behaviours were significantly alleviated. The inhibitory effects of nicotine were reversed by co-administration of mecamylamine (non-selective nicotinic acetylcholine receptor antagonist) and dihydro--erythroidine (selective 42 nicotinic acetylcholine receptor antagonist). Likewise, when 42 nicotinic acetylcholine receptor agonists (TC2559 or ABT418) were administered daily for 4days (day 7-10) after nerve injury, pain behaviours were significantly attenuated. On the other hand, nicotine administered daily for 4days (day 0-3; initiation phase) after nerve injury alleviated pain behaviours, which were antagonized by co-administration of dihydro--erythroidine. TC2559 administered daily for 4days (day 0-3) also attenuated nerve injury-induced pain behaviours. Conclusion The activation of 42 nicotinic acetylcholine receptor expressed on infiltrating macrophages in injured nerves may participate in the relief of PSL-induced neuropathic pain during maintenance and initiation phases.
    Acta Physiologica 12/2014; 213(2). DOI:10.1111/apha.12437 · 4.25 Impact Factor
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    • "In the central nervous system, nicotinic acethylcholine receptors are preferentially located at presynaptic terminals, thereby regulating the release of many neurotransmitters (Wonnacott, 1997; Vizi and Lendvai, 1999; Gotti and Clementi, 2004; Sher et al., 2004) such as glutamate in the rat prefrontal cortex, striatal synaptosomes and nucleus tractus solitarius (Marchi et al., 2002; Zhao et al., 2007; Dickinson et al., 2008). Glutamate excites the hypothalamic paraventricular nucleus (Boudaba et al., 1997; Li et al., 2004), which has been considered to be the control center of the sympatho-adrenomedullary outflow (Swanson and Sawchenko, 1980; Jansen et al., 1995; Kenny et al., 2003). "
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