The nicotinic acetylcholine receptor as a molecular machine for neuromuscular transmission

Bouzat, Cecilia; Mukhtasimova, Nuriya

doi:10.1016/j.cophys.2018.04.008

Cited by 12 publications

(12 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At high concentrations, Aβ may probably inhibit α7 by acting through an allosteric site, different from that of CrV since it does not interfere with its binding. Dual actions as low-efficacy agonists and channel blockers have been described for several compounds acting at different sites of nAChRs (reviewed in Bouzat and Mukhtasimova, 2018; Bouzat and Sine, 2018).…”

Section: Discussionmentioning

confidence: 99%

Molecular Modulation of Human α7 Nicotinic Receptor by Amyloid-β Peptides

Lasala

Fabiani

Corradi

et al. 2019

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

Amyloid β peptide (Aβ) is a key player in the development of Alzheimer’s disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors has been shown to be affected by Aβ soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric Aβ1–40 and Aβ1–42 on human α7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV) revealed that in the presence of Aβ α7 undergoes concentration-dependent conformational changes. Exposure of α7 to 100 pM Aβ changes CrV KD towards that of the desensitized state. However, α7 is still reactive to high carbamylcholine (Carb) concentrations. These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both Aβ and Carb. At 100 nM Aβ, α7 adopts a resting-state-like structure which does not respond to Carb, suggesting stabilization of α7 in a blocked state. In real time, we found that Aβ is capable of eliciting α7 channel activity either in the absence or presence of the positive allosteric modulator (PAM) PNU-120596. Activation by Aβ is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high Aβ concentrations, the mean duration of activation episodes elicited by ACh in the presence of PNU-120596 is significantly reduced, an effect compatible with slow open-channel block. We conclude that Aβ directly affects α7 function by acting as an agonist and a negative modulator. Whereas the capability of low concentrations of Aβ to activate α7 could be beneficial, the reduced α7 activity in the presence of higher Aβ concentrations or its long exposure may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular Modulation of Human α7 Nicotinic Receptor by Amyloid-β Peptides

Lasala

Fabiani

Corradi

et al. 2019

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The only difference between ACh-and bephenium-elicited L-AChR channel activity is that the mean duration of the main closed component is systematically more prolonged with bephenium. Closed times from patches in which either the number of channels is not known or episodes of a single receptor molecule (clusters) cannot be distinguished do not provide relevant kinetic information (Bouzat and Mukhtasimova, 2018;Bouzat and Sine, 2018). However, the duration of the main closed component of recordings of ACh-activated L-AChR channels is relatively constant among patches and is dependent on agonist concentration (Rayes et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Our studies showed that bephenium activates mammalian muscle nAChRs by acting as a weak agonist and a potent channel blocker, thus performing mainly as an inhibitor of ACh-activated channels. The main features, revealing its weak action at mammalian nAChRs, are the lack of clusters of openings over a range of concentrations, which differs from the activation by ACh or full agonists (Akk and Steinbach, 2003;Bouzat and Mukhtasimova, 2018;Bouzat and Sine, 2018), and 10-fold reduced open duration with respect to AChelicited channels. Moreover, if its activity had been tested only at the macroscopic level, its action as a partial agonist would not have been detected.…”

Section: Discussionmentioning

confidence: 99%

“…Nicotinic receptors (nAChRs), which have a key role in muscle contraction and locomotion in vertebrates and invertebrates, are targets of anthelmintic agents. They belong to the Cys-loop receptor family of pentameric ligand-gated ion channels, which contain a large extracellular domain that carries the agonist binding sites and a transmembrane domain that forms the ion channel (Unwin, 2005;Kalamida et al, 2007;Cecchini and Changeux, 2015;Bouzat and Mukhtasimova, 2018). The agonist binding sites are located at subunits interfaces, where one subunit contributes to the principal face and the adjacent one, to the complementary face.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation ofCaenorhabditis elegansLevamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium

et al. 2018

Self Cite

View full text Add to dashboard Cite

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are targets of antiparasitic drugs. Bephenium is an anthelmintic compound whose molecular action in the free-living nematode , which is a model for anthelmintic drug discovery, is poorly known. We explored the effect of bephenium on locomotion and applied single-channel recordings to identify its molecular target, mechanism of action, and selectivity between mammalian and nAChRs. As in parasites, bephenium paralyzes A mutant strain lacking the muscle levamisole-sensitive nAChR (L-AChR) shows full resistance to bephenium, indicating that this receptor is the target site. Bephenium activates L-AChR channels from larvae muscle cells in the micromolar range. Channel activity is similar to that elicited by levamisole, appearing mainly as isolated brief openings. Our analysis revealed that bephenium is an agonist of L-AChR and an open-channel blocker at higher concentrations. It also activates mammalian muscle nAChRs. Opening events are significantly briefer than those elicited by ACh and do not appear in activation episodes at a range of concentrations, indicating that it is a very weak agonist of mammalian nAChRs. Recordings in the presence of ACh showed that bephenium acts as a voltage-dependent channel blocker and a low-affinity agonist. Molecular docking into homology-modeled binding-site interfaces represent the binding mode of bephenium that explains its partial agonism. Given the great diversity of helminth nAChRs and the overlap of their pharmacological profiles, unraveling the basis of drug receptor-selectivity will be required for rational design of anthelmintic drugs.

show abstract

“…All the structural motifs identified here have been shown experimentally to be involved in ligand binding and signal transduction: Loop C is important for binding (e.g. 33,34 ), contributing to binding the ammonium group of the agonists 13,53 ; Loop F plays a role in ligand binding affinity, and specificity 13 ; and the M2-M3 linker is essential for channel gating and communication between domains (e.g. 22,[26][27][28][29][30][39][40][41][42][43][44][45] ), and insertions/deletions of residues in this region directly affect the open-channel lifetime.…”

mentioning

confidence: 81%

A General Mechanism for Signal Propagation in the Nicotinic Acetylcholine Receptor Family

et al. 2019

View full text Add to dashboard Cite

Nicotinic acetylcholine receptors (nAChRs) modulate synaptic activity in the central nervous system. The α7 subtype, in particular, has attracted considerable interest in drug discovery as a target for several conditions, including Alzheimer's disease and schizophrenia. Identifying agonist-induced structural changes underlying nAChR activation is fundamentally important for understanding biological function and rational drug design. Here, extensive equilibrium and nonequilibrium molecular dynamics simulations, enabled by cloud-based high-performance computing, reveal the molecular mechanism by which structural changes induced by agonist unbinding are transmitted within the human α7 nAChR. The simulations reveal the sequence of coupled structural changes involved in driving conformational change responsible for biological function. Comparison with simulations of the α4β2 nAChR subtype identifies

show abstract

The nicotinic acetylcholine receptor as a molecular machine for neuromuscular transmission

Cited by 12 publications

References 97 publications

Molecular Modulation of Human α7 Nicotinic Receptor by Amyloid-β Peptides

Molecular Modulation of Human α7 Nicotinic Receptor by Amyloid-β Peptides

Activation ofCaenorhabditis elegansLevamisole-Sensitive and Mammalian Nicotinic Receptors by the Antiparasitic Bephenium

A General Mechanism for Signal Propagation in the Nicotinic Acetylcholine Receptor Family

Contact Info

Product

Resources

About