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: 9.99). 01/2005; 74(6):363-96. DOI: 10.1016/j.pneurobio.2004.09.006
Source: PubMed


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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    • "a Refer to supplementary data on in house verification. of these processes and lead to exaggerated/altered physiological activity (Gotti and Clementi, 2004). Although various studies with animal models of nicotine exposure exist in the literature, those examining nAChR expression are limited to prenatal, adolescent, and adult brain and only examine mRNA and receptor binding (summarized in Supplementary Tables 1 and 2). "
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    ABSTRACT: Postnatal exposure to cigarette smoke during infancy is associated with increased number of respiratory illnesses, impaired pulmonary function, and the occurrence of Sudden Infant Death Syndrome (SIDS). It is also associated with reduced cognitive functioning and attention deficits in childhood. Nicotine, the major neurotoxic component of cigarette smoke, induces its actions by binding to nicotinic acetylcholine receptors (nAChR). Using a piglet model of postnatal nicotine exposure, we studied the immunohistochemical expression of nAChR subunits α2, α3, α4, α5, α7, α9, β1 and β2 in the brainstem medulla and the hippocampus, given the role of these structures in cardiorespiratory control and cognition, respectively. We compared piglets exposed postnatally to 2 mg/kg/day nicotine for 14 days (n= 14: 7 males: 7 females) to controls (n= 14: 7 males: 7 females). In the hippocampus, decreased expression was seen for α3 in CA1 (p= 0.017), α9 in CA1 (p<. 0.001) and CA2 (p< 0.001), β1 in CA1 (p= 0.001) and CA2 (p= 0.001) and β2 in CA3 (p= 0.036). In the medulla, the nucleus of the spinal trigeminal tract had increased α2 and α4; vestibular nucleus increased α2 and α3, and decreased α4; hypoglossal decreased α3 and β1; dorsal motor nucleus of the vagus decreased α4 and β1. This is the first demonstration that non-classical nAChR subunits are affected by postnatal nicotine in the developing brain, and the implications are discussed.
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    • "g . , α4β2 ; Figure 1 ; Gotti and Clementi , 2004 ; Kalamida et al . , 2007 ; Hurst et al . "
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    ABSTRACT: Nicotine addiction, the result of tobacco use, leads to over six million premature deaths world-wide per year, a number that is expected to increase by a third within the next two decades. While more than half of smokers want and attempt to quit, only a small percentage of smokers are able to quit without pharmacological interventions. Therefore, over the past decades, researchers in academia and the pharmaceutical industry have focused their attention on the development of more effective smoking cessation therapies, which is now a growing 1.9 billion dollar market. Because the role of neuronal nicotinic acetylcholine receptors (nAChR) in nicotine addiction is well established, nAChR based therapeutics remain the leading strategy for smoking cessation. However, the development of neuronal nAChR drugs that are selective for a nAChR subpopulation is challenging, and only few neuronal nAChR drugs are clinically available. Among the many neuronal nAChR subtypes that have been identified in the brain, the α4β2 subtype is the most abundant and plays a critical role in nicotine addiction. Here, we review the role of neuronal nAChRs, especially the α4β2 subtype, in the development and treatment of nicotine addiction. We also compare available smoking cessation medications and other nAChR orthosteric and allosteric ligands that have been developed with emphasis on the difficulties faced in the development of clinically useful compounds with high nAChR subtype selectivity.
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    • "Among a number of novel approaches to pain relief currently under investigation, nicotinic acetylcholine receptors (nAChRs) hold considerable potential as therapeutic targets for the development of analgesic drugs [7]. The neuronal nicotinic acethylcholine receptors are prototypic ligand-gated ion channel receptors that are widely expressed through the central and peripheral nervous system and mediate fast synaptic transmission [8] [9]. Neuronal nAChRs are pentameric proteins comprising either combinations of two different types of subunit (a and b) or five copies of the same a subunit symmetrically arranged around a central ion pore. "
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    ABSTRACT: New analogues (3a-l) of the previously described α4β2 selective ligand 3-(6-halopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptanes (2a,b) have been synthesized and their binding activity for neuronal acetylcholine receptor subtypes α4β2 and α7 were assayed. Six of these compounds (3a,b,c,j,k and l) showed high affinity and selectivity for α4β2 receptors. The phenylpyridyl-diazabicycloheptane 3c displayed Ki value of 11.17 pM for α4β2, in line with that of the halogenated homologues 3a,b, although it was characterized by an improved selectivity (Ki = 17 μM for α7 receptors). The influence of substitutions on the phenylpyridyl moiety on binding at both α4β2 and α7 receptors has been examined through the Topliss decision tree analysis. Substitution with electron-donating groups (as CH3 and OCH3) resulted in a good affinity for α4β2 receptors and substantially no affinity for α7. Amongst all the tested phenyl-substituted compounds, the p-NO2-phenyl substituted analogue 3j exhibited the highest α4β2 affinity, with Ki value comparable to that of 3c. Intrinsic α4β2 receptor mediated activity in [(3)H]-DA release assay was showed by compound 3a as well as by the reference analogue 2a, whereas phenyl substituted derivative 3c exhibited α4β2 antagonist activity.
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