Ion channels gated by acetylcholine and serotonin: structures, biology, and drug discovery

Wu, Zhongshan; Cheng, Hao; Jiang, Yi; Melcher, Karsten; Xu, H. Eric

doi:10.1038/aps.2015.66

Cited by 57 publications

(57 citation statements)

References 89 publications

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“…In particular, for ligand gated ion channels (LGICs), the univocal determination of quantities to discriminate between conductive 2 and non-conductive states gained new boost in recent years, thanks to X-ray crystallographic structures for a small number of channels and their homologs, as well as computationallyderived structural models. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] The structural characterization of different non-conductive states is especially complex, as they all have in common a non-conductive pore in the transmembrane domain (TMD).…”

Section: Introductionmentioning

confidence: 99%

Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study

Chiodo

Malliavin

Giuffrida

et al. 2018

J. Chem. Inf. Model.

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Journal of Chemical Information and Modeling gated ion channels (LGICs), are membrane proteins present in neurons and at neuromuscular junctions. They are responsible for signal transmission, and their function is regulated by neurotransmitters, agonists and antagonists drugs. A detailed knowledge of their conformational transition in response to ligand binding is critical to understand the basis of ligand-receptor interaction, in view of new pharmacological approaches to control receptor activity. However, the scarcity of experimentally derived structures of human channels makes this perspective extremely challenging. To contribute overcoming this issue, we have recently reported structural models for the open and the desensitized states of the human α7 nicotinic receptor. Here, we provide all-atom structural models of the same receptor in two different non-conductive states. The first structure, built via homology modeling and relaxed with extensive Molecular Dynamics simulations, represents the receptor bound to the natural antagonist α-conotoxin ImI. After comparison with available experimental data and computational models of other eukaryotic LGICs, we deem it consistent with the "closed-locked" state. The second model, obtained with simulations from the spontaneous relaxation of the open, agonist-bound α7 structure after ligand removal, recapitulates the characteristics of the apo-resting state of the receptor. These results add to our previous work on the active and desensitized state conformations, contributing to the structural characterization of the conformational landscape of the human α7 receptor, and suggesting benchmarks to discriminate among conformations found in experiments or in simulations of LGICs. In particular key interactions at the interface between the extracellular domain and the transmembrane domain are identified, that could be critical to the α7 receptor function.

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Section: Introductionmentioning

confidence: 99%

Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study

Chiodo

Malliavin

Giuffrida

et al. 2018

J. Chem. Inf. Model.

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“…This receptor mediates fast excitatory synaptic transmission in both peripheral and central nervous systems and it is essential for evoking skeletal muscle contraction (Albuquerque et al, 2009). In the past few years, a growing number of ligands have been developed to selectively modulate nAChRs, as potential tools for the treatment of different pathophysiological processes, including addiction, depression, cognitive alterations, motor dysfunctions, inflammation, and pain (Taly et al, 2009; Hurst et al, 2013; Wu et al, 2015), indicating that nAChRs constitute a chief therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Muscle-Type Nicotinic Receptor Modulation by 2,6-Dimethylaniline, a Molecule Resembling the Hydrophobic Moiety of Lidocaine

Alberola-Die

Fernández‐Ballester

González-Ros

et al. 2016

Front. Mol. Neurosci.

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To identify the molecular determinants responsible for lidocaine blockade of muscle-type nAChRs, we have studied the effects on this receptor of 2,6-dimethylaniline (DMA), which resembles lidocaine’s hydrophobic moiety. Torpedo marmorata nAChRs were microtransplanted to Xenopus oocytes and currents elicited by ACh (IACh), either alone or co-applied with DMA, were recorded. DMA reversibly blocked IACh and, similarly to lidocaine, exerted a closed-channel blockade, as evidenced by the enhancement of IACh blockade when DMA was pre-applied before its co-application with ACh, and hastened IACh decay. However, there were marked differences among its mechanisms of nAChR inhibition and those mediated by either the entire lidocaine molecule or diethylamine (DEA), a small amine resembling lidocaine’s hydrophilic moiety. Thereby, the IC50 for DMA, estimated from the dose-inhibition curve, was in the millimolar range, which is one order of magnitude higher than that for either DEA or lidocaine. Besides, nAChR blockade by DMA was voltage-independent in contrast to the increase of IACh inhibition at negative potentials caused by the more polar lidocaine or DEA molecules. Accordingly, virtual docking assays of DMA on nAChRs showed that this molecule binds predominantly at intersubunit crevices of the transmembrane-spanning domain, but also at the extracellular domain. Furthermore, DMA interacted with residues inside the channel pore, although only in the open-channel conformation. Interestingly, co-application of ACh with DEA and DMA, at their IC50s, had additive inhibitory effects on IACh and the extent of blockade was similar to that predicted by the allotopic model of interaction, suggesting that DEA and DMA bind to nAChRs at different loci. These results indicate that DMA mainly mimics the low potency and non-competitive actions of lidocaine on nAChRs, as opposed to the high potency and voltage-dependent block by lidocaine, which is emulated by the hydrophilic DEA. Furthermore, it is pointed out that the hydrophobic (DMA) and hydrophilic (DEA) moieties of the lidocaine molecule act differently on nAChRs and that their separate actions taken together account for most of the inhibitory effects of the whole lidocaine molecule on nAChRs.

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“…Unfortunately, similar to other ligand-gated ion channels (LGICs) such as 5-HT 3 and GABA A , there is no available high-resolution crystal structure of the α 7 receptor. However, some evidence-based hypotheses [26][27][28] and theoretical models [29][30][31] have been developed.…”

Section: Original Articlementioning

confidence: 99%

Discovery, synthesis, biological evaluation and structure-based optimization of novel piperidine derivatives as acetylcholine-binding protein ligands

Shen

Yang

et al. 2016

Acta Pharmacol Sin

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The homomeric α7 nicotinic receptor (α7 nAChR) is widely expressed in the human brain that could be activated to suppress neuroinflammation, oxidative stress and neuropathic pain. Consequently, a number of α7 nAChR agonists have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. However, high-resolution crystal structure of the full-length α7 receptor is thus far unavailable. Since acetylcholine-binding protein (AChBP) from Lymnaea stagnalis is most closely related to the α-subunit of nAChRs, it has been used as a template for the N-terminal domain of α-subunit of nAChR to study the molecular recognition process of nAChRligand interactions, and to identify ligands with potential nAChR-like activities. Here we report the discovery and optimization of novel acetylcholine-binding protein ligands through screening, structure-activity relationships and structure-based design. We manually screened in-house CNS-biased compound library in vitro and identified compound 1, a piperidine derivative, as an initial hit with moderate binding affinity against AChBP (17.2% inhibition at 100 nmol/L). During the 1st round of optimization, with compound 2 (21.5% inhibition at 100 nmol/L) as the starting point, 13 piperidine derivatives with different aryl substitutions were synthesized and assayed in vitro. No apparent correlation was demonstrated between the binding affinities and the steric or electrostatic effects of aryl substitutions for most compounds, but compound 14 showed a higher affinity (K i =105.6 nmol/L) than nicotine (K i =777 nmol/L). During the 2nd round of optimization, we performed molecular modeling of the putative complex of compound 14 with AChBP, and compared it with the epibatidine-AChBP complex. The results suggested that a different piperidinyl substitution might confer a better fit for epibatidine as the reference compound. Thus, compound 15 was designed and identified as a highly affinitive acetylcholinebinding protein ligand. In this study, through two rounds of optimization, compound 15 (K i =2.8 nmol/L) has been identified as a novel, piperidine-based acetylcholine-binding protein ligand with a high affinity.

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Ion channels gated by acetylcholine and serotonin: structures, biology, and drug discovery

Cited by 57 publications

References 89 publications

Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study

Closed-Locked and Apo-Resting State Structures of the Human α7 Nicotinic Receptor: A Computational Study

Muscle-Type Nicotinic Receptor Modulation by 2,6-Dimethylaniline, a Molecule Resembling the Hydrophobic Moiety of Lidocaine

Discovery, synthesis, biological evaluation and structure-based optimization of novel piperidine derivatives as acetylcholine-binding protein ligands

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