scholarly journals Structural correlates of human muscle nicotinic acetylcholine receptor subunit assembly mediated by δ(+) interface residues

2020 ◽  
Author(s):  
Max Epstein ◽  
Susan Maxwell ◽  
Thomas J. Piggot ◽  
David Beeson ◽  
Isabel Bermudez ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Dynamical Behavior ◽  
Human Muscle ◽  
Amino Acid Residues ◽  
Nicotinic Acetylcholine ◽  
Specific Amino Acid ◽  
Functional Differences ◽  
Electrode Voltage ◽  
Dynamics Simulations

AbstractMuscle nicotinic acetylcholine receptors are a class of heteropentameric ligand-gated cation channels with constituent subunits adopting a fixed stoichiometric arrangement. The specific amino acid residues that govern subunit ordering are however, only partially understood. By integrating all-atom molecular dynamics simulations, bioinformatics, two-electrode voltage clamp electrophysiology and 125I-α-bungarotoxin assays of chimeric nAChR subunits, we identify residues across the extracellular, transmembrane and extended M4 helix of the δ subunit that make structural signatures that contribute to intransigent assembly rules. Furthermore, functional differences observed in α2δ2β receptors can be rationalized by changes in dynamical behavior that manifest themselves at the agonist binding site.

scholarly journals Tetrapeptide Ac-HAEE-NH2 Protects α4β2 nAChR from Inhibition by Aβ

2020 ◽  
Vol 21 (17) ◽  
pp. 6272
Author(s):  
Evgeny P. Barykin ◽  
Aleksandra I. Garifulina ◽  
Anna P. Tolstova ◽  
Anastasia A. Anashkina ◽  
Alexei A. Adzhubei ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Cholinergic Neurons ◽  
Xenopus Laevis Oocytes ◽  
Aβ Peptide ◽  
Amino Acid Residues ◽  
Cholinergic Dysfunction ◽  
Potential Binding ◽  
Electrode Voltage ◽  
Potential Binding Site

The cholinergic deficit in Alzheimer’s disease (AD) may arise from selective loss of cholinergic neurons caused by the binding of Aβ peptide to nicotinic acetylcholine receptors (nAChRs). Thus, compounds preventing such an interaction are needed to address the cholinergic dysfunction. Recent findings suggest that the 11EVHH14 site in Aβ peptide mediates its interaction with α4β2 nAChR. This site contains several charged amino acid residues, hence we hypothesized that the formation of Aβ-α4β2 nAChR complex is based on the interaction of 11EVHH14 with its charge-complementary counterpart in α4β2 nAChR. Indeed, we discovered a 35HAEE38 site in α4β2 nAChR, which is charge-complementary to 11EVHH14, and molecular modeling showed that a stable Aβ42-α4β2 nAChR complex could be formed via the 11EVHH14:35HAEE38 interface. Using surface plasmon resonance and bioinformatics approaches, we further showed that a corresponding tetrapeptide Ac-HAEE-NH2 can bind to Aβ via 11EVHH14 site. Finally, using two-electrode voltage clamp in Xenopus laevis oocytes, we showed that Ac-HAEE-NH2 tetrapeptide completely abolishes the Aβ42-induced inhibition of α4β2 nAChR. Thus, we suggest that 35HAEE38 is a potential binding site for Aβ on α4β2 nAChR and Ac-HAEE-NH2 tetrapeptide corresponding to this site is a potential therapeutic for the treatment of α4β2 nAChR-dependent cholinergic dysfunction in AD.

scholarly journals Identifying Key Amino Acid Residues That Affect α-Conotoxin AuIB Inhibition of α3β4 Nicotinic Acetylcholine Receptors

2013 ◽  
Vol 288 (48) ◽  
pp. 34428-34442 ◽  
Author(s):  
Anton A. Grishin ◽  
Hartmut Cuny ◽  
Andrew Hung ◽  
Richard J. Clark ◽  
Andreas Brust ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Amino Acid Residues ◽  
Nicotinic Acetylcholine

Contrasting Actions of Philanthotoxin-343 and Philanthotoxin-(12) on Human Muscle Nicotinic Acetylcholine Receptors

2003 ◽  
Vol 64 (4) ◽  
pp. 954-964 ◽  
Author(s):  
Tim J. Brier ◽  
Ian R. Mellor ◽  
Denis B. Tikhonov ◽  
Ioana Neagoe ◽  
Zuoyi Shao ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Human Muscle ◽  
Nicotinic Acetylcholine

aMolecular Insights into Stereoselective Binding of Quinuclidine-Triazole Derivatives to a7 and a3b4 Nicotinic Acetylcholine Receptors

2018 ◽  
Author(s):  
Kuntarat Arunrungvichian ◽  
Jiradanai Sarasamkan ◽  
Gerrit Schüürmann ◽  
Peter Brust ◽  
Opa Vajragupta
Keyword(s):  
Amino Acid ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Binding Pocket ◽  
Amino Acid Residues ◽  
Nicotinic Acetylcholine ◽  
Selective Binding ◽  
Subtype Selectivity ◽  
Nachr Subtype ◽  
Primary Determinant

An investigation on the selective binding of six quinuclidine-triazole enantiomeric pairs to nicotinic acetylcholine receptor (nAChR) subtypes, (S)-enantiomers for a3b4-nAChR and its (R)-counterpart for a7-nAChR, was performed in silico to provide the insight into the molecular basis for subtype discrimination of the quinuclidine-triazole enantiomers. The homology modeling and molecular docking analyses revealed that unique amino acid residues in the complementary subunit of nAChR subtypes are related to a high subtype selectivity profile. One non-conserved residue AspB173 in a complementary b4-subunit of the a3b4-nAChR binding pocket was found to be a primary determinant for the a3b4 selectivity of the quinuclidine-triazole chemotype as evidenced by the more pronounced enantioselectivity of (S)-enantiomers for the a3b4 nAChR, 47-326 times greater than its corresponding (R)-enantiomers. For (R)-enantiomers toward the a7 subtype, the interacting amino acid residues were the conserved TyrA93 and TrpA149 and TrpB55, leading to a lesser degree of stereoselectivity. The interaction with non-conserved amino acid residues in the complementary subunit of nAChR subtypes appeared to be the determinant for the nAChR subtype-selective binding, particularly at the heteropentameric subtype.

scholarly journals Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations

Marine Drugs ◽  
2020 ◽  
Vol 18 (7) ◽  
pp. 349
Author(s):  
Jierong Wen ◽  
David J. Adams ◽  
Andrew Hung
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neurological Diseases ◽  
Nicotinic Acetylcholine ◽  
Binding Interface ◽  
C Terminus ◽  
Dynamics Simulations ◽  
The Individual ◽  
Carboxy Terminal ◽  
Subtype Selective

Notably, α-conotoxins with carboxy-terminal (C-terminal) amidation are inhibitors of the pentameric nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets for neurological diseases and disorders. The (α3)2(β2)3 nAChR subunit arrangement comprises a pair of α3(+)β2(−) and β2(+)α3(−) interfaces, and a β2(+)β2(−) interface. The β2(+)β2(−) interface has been suggested to have higher agonist affinity relative to the α3(+)β2(−) and β2(+)α3(−) interfaces. Nevertheless, the interactions formed by these subunit interfaces with α-conotoxins are not well understood. Therefore, in order to address this, we modelled the interactions between α-conotoxin LsIA and the α3β2 subtype. The results suggest that the C-terminal carboxylation of LsIA predominantly influenced the enhanced contacts of the conotoxin via residues P7, P14 and C17 on LsIA at the α3(+)β2(−) and β2(+)α3(−) interfaces. However, this enhancement is subtle at the β2(+)β2(−) site, which can compensate the augmented interactions by LsIA at α3(+)β2(−) and β2(+)α3(−) binding sites. Therefore, the divergent interactions at the individual binding interface may account for the minor changes in binding affinity to α3β2 subtype by C-terminal carboxylation of LsIA versus its wild type, as shown in previous experimental results. Overall, these findings may facilitate the development of new drug leads or subtype-selective probes.

scholarly journals Molecular Regulation of α3β4 Nicotinic Acetylcholine Receptors by Lupeol in Cardiovascular System

2020 ◽  
Vol 21 (12) ◽  
pp. 4329
Author(s):  
Sanung Eom ◽  
Chaelin Kim ◽  
Hye Duck Yeom ◽  
Jaeeun Lee ◽  
Shinhui Lee ◽  
...  
Keyword(s):  
Natural Products ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Animal Experiments ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Nicotinic Acetylcholine ◽  
Electrode Voltage ◽  
Treatment Of Hypertension ◽  
Nicotine Acetylcholine Receptor

Cardiovascular disease (CVD) occurs globally and has a high mortality rate. The highest risk factor for developing CVD is high blood pressure. Currently, natural products are emerging for the treatment of hypertension to avoid the side effects of drugs. Among existing natural products, lupeol is known to be effective against hypertension in animal experiments. However, there exists no study regarding the molecular physiological evidence against the effects of lupeol. Consequently, we investigated the interaction of lupeol with α3β4 nicotinic acetylcholine receptors (nAChRs). In this study, we performed a two-electrode voltage-clamp technique to investigate the effect of lupeol on the α3β4 nicotine acetylcholine receptor using the oocytes of Xenopus laevis. Coapplication of acetylcholine and lupeol inhibited the activity of α3β4 nAChRs in a concentration-dependent, voltage-independent, and reversible manner. We also conducted a mutational experiment to investigate the influence of residues of the α3 and β4 subunits on lupeol binding with nAChRs. Double mutants of α3β4 (I37A/N132A), nAChRs significantly attenuated the inhibitory effects of lupeol compared to wild-type α3β4 nAChRs. A characteristic of α3β4 nAChRs is their effect on transmission in the cardiac sympathetic ganglion. Overall, it is hypothesized that lupeol lowers hypertension by mediating its effects on α3β4 nAChRs. The interaction between lupeol and α3β4 nAChRs provides evidence against its effect on hypertension at the molecular-cell level. In conclusion, the inhibitory effect of lupeol is proposed as a novel therapeutic approach involving the antihypertensive targeting of α3β4 nAChRs. Furthermore, it is proposed that the molecular basis of the interaction between lupeol and α3β4 nAChRs would be helpful in cardiac-pharmacology research and therapeutics.

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