Diversity of native nicotinic receptor subtypes in mammalian brain

Zoli, Michèle; Pistillo, Francesco; Gotti, Cecilia

doi:10.1016/j.neuropharm.2014.11.003

Cited by 228 publications

(241 citation statements)

References 115 publications

(140 reference statements)

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“…As shown in the figure, in a7, this region contains determinants of channel conductance (Andersen et al, , 2013 and mediates several intracellular signals (Paulo et al, 2009;Jones et al, 2010). (Liu et al, 2009(Liu et al, , 2012Moretti et al, 2014;Thomsen et al, 2015;Zoli et al, 2015). Interestingly, a7b2 are highly sensitive to blockade by Ab1-42, suggesting that they may play a unique role in the neuropathology of Alzheimer disease (Liu et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

2016

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The nicotinic acetylcholine receptor (nAChR) belongs to a superfamily of pentameric ligand-gated ion channels involved in many physiologic and pathologic processes. Among nAChRs, receptors comprising the a7 subunit are unique because of their high Ca 21 permeability and fast desensitization. nAChR agonists elicit a transient ion flux response that is further sustained by the release of calcium from intracellular sources. Owing to the dual ionotropic/metabotropic nature of a7 receptors, signaling pathways are activated. The a7 subunit is highly expressed in the nervous system, mostly in regions implicated in cognition and memory and has therefore attracted attention as a novel drug target. Additionally, its dysfunction is associated with several neuropsychiatric and neurologic disorders, such as schizophrenia and Alzheimer's disease. a7 is also expressed in non-neuronal cells, particularly immune cells, where it plays a role in immunity, inflammation, and neuroprotection. Thus, a7 potentiation has emerged as a therapeutic strategy for several neurologic and inflammatory disorders. With unique activation properties, the receptor is a sensitive drug target carrying different potential binding sites for chemical modulators, particularly agonists and positive allosteric modulators. Although macroscopic and singlechannel recordings have provided significant information about the underlying molecular mechanisms and binding sites of modulatory compounds, we know just the tip of the iceberg. Further concerted efforts are necessary to effectively exploit a7 as a drug target for each pathologic situation. In this article, we focus mainly on the molecular basis of activation and drug modulation of a7, key pillars for rational drug design.

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Section: Introductionmentioning

confidence: 99%

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

2016

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“…16 Nicotine's action requires numerous nAChRs subtypes segregated into high-affinity heteromeric nAChRs containing the β2 subunit (β2*) and low-affinity homomeric α7 nAChRs. 17 They determine the sensitivity of the reward system to a minimum dose of nicotine necessary for VTA DA cell activation and thus nicotine reinforcement. 18 VTA nAChRs subtypes are present on GABA and DA neurons, as well as on excitatory inputs, which results in a fine tuning of DA neuronal activity.…”

Section: Introductionmentioning

confidence: 99%

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

et al. 2017

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Epidemiological studies report strong association between mood disorders and tobacco addiction. This high comorbidity requires adequate treatment but the underlying mechanisms are unknown. We demonstrate that nicotine exposure, independent of drug withdrawal effects, increases stress sensitivity, a major risk factor in mood disorders. Nicotine and stress concur to induce long-lasting cellular adaptations within the dopamine (DA) system. This interplay is underpinned by marked remodeling of nicotinic systems, causing increased ventral tegmental area (VTA) DA neurons' activity and stress-related behaviors, such as social aversion. Blocking β2 or α7 nicotinic acetylcholine receptors (nAChRs) prevents, respectively, the development and the expression of social stress-induced neuroadaptations; conversely, facilitating α7 nAChRs activation specifically in the VTA promotes stress-induced cellular and behavioral maladaptations. Our work unravels a complex nicotine-stress bidirectional interplay and identifies α7 nAChRs as a promising therapeutic target for stress-related psychiatric disorders.

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“…They belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC), which includes γ-aminobutyric acid (GABA A and GABA C ), glycine, and serotonin (5-HT 3 ) receptors (8). The neuronal nAChR subfamily consists of numerous homomeric and heteromeric pentameric assemblies, formed by α (α2-α10) and β (β2-β4) subunits, distributed ubiquitously in the brain (9). Because of their considerable homology, especially in their binding sites, designing a novel drug specific for one type of nAChR can be a challenging procedure and requires the addition of more structural information.…”

mentioning

confidence: 99%

Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer

Kouvatsos

Giastas

Chroni-Tzartou

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In this study we report the X-ray crystal structure of the extracellular domain (ECD) of the human neuronal α2 nicotinic acetylcholine receptor (nAChR) subunit in complex with the agonist epibatidine at 3.2 Å. Interestingly, α2 was crystallized as a pentamer, revealing the intersubunit interactions in a wild type neuronal nAChR ECD and the full ligand binding pocket conferred by two adjacent α subunits. The pentameric assembly presents the conserved structural scaffold observed in homologous proteins, as well as distinctive features, providing unique structural information of the binding site between principal and complementary faces. Structure-guided mutagenesis and electrophysiological data confirmed the presence of the α2(+)/α2(−) binding site on the heteromeric low sensitivity α2β2 nAChR and validated the functional importance of specific residues in α2 and β2 nAChR subunits. Given the pathological importance of the α2 nAChR subunit and the high sequence identity with α4 (78%) and other neuronal nAChR subunits, our findings offer valuable information for modeling several nAChRs and ultimately for structurebased design of subtype specific drugs against the nAChR associated diseases.cys-loop receptors | α2β2 nAChR | X-ray crystallography | ligand-gated ion channel

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Diversity of native nicotinic receptor subtypes in mammalian brain

Cited by 228 publications

References 115 publications

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound α2 homopentamer

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