Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system

Taly, Antoine; Corringer, Pierre‐Jean; Guédin, Denis; Lestage, Pierre; Changeux, Jean‐Pierre

doi:10.1038/nrd2927

Cited by 626 publications

(637 citation statements)

References 281 publications

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“…The model assumes that the defining parameters for BP are not altered by the change in endogenous competition itself. Given that equilibrium is not achieved during challenge paradigms, that affinities can be altered by endogenous neurotransmitter, e.g., by cooperative binding (Frankle et al, 2009;Taly et al, 2009), and that B avail can change by receptor-trafficking mechanisms, this cannot be guaranteed. Modified from Laruelle (2000).…”

Section: Development Of Radiotracers To Image Endogenous 5-htmentioning

confidence: 99%

Measuring Endogenous 5-HT Release by Emission Tomography: Promises and Pitfalls

Paterson

Tyacke

Nutt

et al. 2010

J Cereb Blood Flow Metab

128

137

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Molecular in vivo neuroimaging techniques can be used to measure regional changes in endogenous neurotransmitters, evoked by challenges that alter synaptic neurotransmitter concentration. This technique has most successfully been applied to the study of endogenous dopamine release using positron emission tomography, but has not yet been adequately extended to other neurotransmitter systems. This review focuses on how the technique has been applied to the study of the 5-hydroxytryptamine (5-HT) system. The principles behind visualising fluctuations in neurotransmitters are introduced, with reference to the dopaminergic system. Studies that aim to image acute, endogenous 5-HT release or depletion at 5-HT receptor targets are summarised, with particular attention to studies in humans. Radiotracers targeting the 5-HT 1A , 5-HT 2A , and 5-HT 4 receptors and the serotonin reuptake transporter have been explored for their sensitivity to 5-HT fluctuations, but with mixed outcomes; tracers for these targets cannot reliably image endogenous 5-HT in humans. Shortcomings in our basic knowledge of the mechanisms underlying changes in binding potential are addressed, and suggestions are made as to how the selection of targets, radiotracers, challenge paradigms, and experimental design might be optimised to improve our chances of successfully imaging endogenous neurotransmitters in the future.

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Section: Development Of Radiotracers To Image Endogenous 5-htmentioning

confidence: 99%

Measuring Endogenous 5-HT Release by Emission Tomography: Promises and Pitfalls

Paterson

Tyacke

Nutt

et al. 2010

J Cereb Blood Flow Metab

128

137

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“…This subunit has important roles in brain development and neuron differentiation and migration (Gotti et al 2009;Taly et al 2009), and its chromosomal locus was associated in humans with developmental and neurological disorders (Ben-Shachar et al 2009;Consortium 2008;Helbig et al 2009;Miller et al 2009;Sharp et al 2008;Shinawi et al 2009;Stefansson et al 2008). Despite the importance of the α7 nAChR subunit, its deficiency results in viable, anatomically normal α7-null mice (Orr-Urtreger et al 1997;Paylor et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Seventeen nAChR subunit encoding genes have been identified. Of them, nine α and three β subunits are expressed in the brain (Taly et al 2009). The nAChRs have been implicated in complex diseases affecting the nervous system, including epilepsy, schizophrenia, developmental disorders, and aging-associated neurodegenerative diseases such as AD and PD (Freedman et al 2001;Steinlein et al 1995).…”

Section: Introductionmentioning

confidence: 99%

The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

Kedmi

Orr-Urtreger

2010

AGE

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Aging is accompanied by expression changes in multiple genes, and the brain is one of the tissues most vulnerable to aging. Since the α7 nicotinic acetylcholine receptor (nAChR) subunit has been associated with neurodevelopmental disorders and cognitive decline during aging, we hypothesized that its absence might affect gene expression profiles in aged brains. To study whether transcriptional changes occur due to aging, α7 deficiency, or both, we analyzed whole-brain transcriptomes of young (8 weeks) and aged (2 years) α7-deficient and wild-type control mice, using Mouse Genome 430 2.0 microarray. Highly significant expression changes were detected in 47 and 1,543 genes [after Bonferroni and false discovery rate (FDR) correction] in the brains of aged mice compared to young mice, regardless of their genotype. These included genes involved in immune system function and ribosome structure, as well as genes that were previously demonstrated as differentially expressed in aging human brains. Genotype-dependent changes were detected in only three genes, Chrna7 which encodes the α7 nAChR subunit, and two closely linked genes, likely due to a "mouse background effect." Expression changes dependent on age-genotype interaction were detected in 207 genes (with a low significance threshold). Age-dependent differential expression levels were approved in all nine genes that were chosen for validation by real-time RT-PCR. Our results suggest that the robust effect of aging on brain transcription clearly overcomes the almost negligible effect of α7 nAChR subunit deletion and that germ line deficiency of this subunit has a minor effect on brain expression profile in aged mice.

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“…Each of these therapies has a modest success of 20%−30% abstinence one year after quitting. 12−14 The target site of many nAChR drug discovery programs is the orthosteric (agonist binding) site of nAChRs, 6,15 and some laboratories have had some success in identifying molecules that show some selectivity using this approach. 16,17 One difficulty with this strategy is the high degree of conservation of the orthosteric site among the various nAChR subtypes, making it difficult to develop subtype-selective drugs.…”

mentioning

confidence: 99%

Defining the Putative Inhibitory Site for a Selective Negative Allosteric Modulator of Human α4β2 Neuronal Nicotinic Receptors

Henderson

González-Cestari

et al. 2012

ACS Chem. Neurosci.

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Neuronal nicotinic receptors (nAChRs) have been implicated in several diseases and disorders such as autism spectrum disorders, Alzheimer's disease, Parkinson's disease, epilepsy, and nicotine addiction. To understand the role of nAChRs in these conditions, it would be beneficial to have selective molecules that target specific nAChRs in vitro and in vivo. Our laboratory has previously identified a novel allosteric site on human α4β2 nAChRs using a series of computational and in vitro approaches. At this site, we have identified negative allosteric modulators that selectively inhibit human α4β2 nAChRs, a subtype implicated in nicotine addiction. This study characterizes the allosteric site via site-directed mutagenesis. Three amino acids (Phe118, Glu60, and Thr58) on the β2 subunit were shown to participate in the inhibitory properties of the selective antagonist KAB-18 and provided insights into its antagonism of human α4β2 nAChRs. SAR studies with KAB-18 analogues and various mutant α4β2 nAChRs also provided information concerning how different physiochemical features influence the inhibition of nAChRs through this allosteric site. Together, these studies identify the amino acids that contribute to the selective antagonism of human α4β2 nAChRs at this allosteric site. Finally, these studies define the physiochemical features of ligands that influence interaction with specific amino acids in this allosteric site.

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Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system

Cited by 626 publications

References 281 publications

Measuring Endogenous 5-HT Release by Emission Tomography: Promises and Pitfalls

Measuring Endogenous 5-HT Release by Emission Tomography: Promises and Pitfalls

The effects of aging vs. α7 nAChR subunit deficiency on the mouse brain transcriptome: aging beats the deficiency

Defining the Putative Inhibitory Site for a Selective Negative Allosteric Modulator of Human α4β2 Neuronal Nicotinic Receptors

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