scholarly journals Effect of Methionine Oxidation and Substitution of α-Conotoxin TxID on α3β4 Nicotinic Acetylcholine Receptor

Marine Drugs ◽  
2018 ◽  
Vol 16 (6) ◽  
pp. 215 ◽  
Author(s):  
Jie Ren ◽  
Rui Li ◽  
Jiong Ning ◽  
Xiaopeng Zhu ◽  
Dongting Zhangsun ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Methionine Sulfoxide ◽  
Nicotinic Acetylcholine ◽  
Methionine Residue ◽  
Electrophysiological Recordings ◽  
Nachr Subtype ◽  
Potent Inhibition ◽  
Dynamics Simulations ◽  
The Impact

α-Conotoxin TxID was discovered from Conus textile by gene cloning, which has 4/6 inter-cysteine loop spacing and selectively inhibits α3β4 nicotinic acetylcholine receptor (nAChR) subtype. However, TxID is susceptible to modification due to it containing a methionine (Met) residue that easily forms methionine sulfoxide (MetO) in oxidative environment. In this study, we investigated how Met-11 and its derivatives affect the activity of TxID using a combination of electrophysiological recordings and molecular modelling. The results showed most TxID analogues had substantially decreased activities on α3β4 nAChR with more than 10-fold potency loss and 5 of them demonstrated no inhibition on α3β4 nAChR. However, one mutant, [M11I]TxID, displayed potent inhibition at α3β4 nAChR with an IC50 of 69 nM, which only exhibited 3.8-fold less compared with TxID. Molecular dynamics simulations were performed to expound the decrease in the affinity for α3β4 nAChR. The results indicate replacement of Met with a hydrophobic moderate-sized Ile in TxID is an alternative strategy to reduce the impact of Met oxidation, which may help to redesign conotoxins containing methionine residue.

scholarly journals Mechanism of calcium potentiation of the α7 nicotinic acetylcholine receptor

2020 ◽  
Vol 152 (9) ◽  
Author(s):  
Kathiresan Natarajan ◽  
Nuriya Mukhtasimova ◽  
Jeremías Corradi ◽  
Matías Lasala ◽  
Cecilia Bouzat ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Single Channel ◽  
Structural Motif ◽  
Site Mutation ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Low Concentrations ◽  
Channel Opening ◽  
Dynamics Simulations

The α7 nicotinic acetylcholine receptor (nAChR) is among the most abundant types of nAChR in the brain, yet the ability of nerve-released ACh to activate α7 remains enigmatic. In particular, a major population of α7 resides in extra-synaptic regions where the ACh concentration is reduced, owing to dilution and enzymatic hydrolysis, yet ACh shows low potency in activating α7. Using high-resolution single-channel recording techniques, we show that extracellular calcium is a powerful potentiator of α7 activated by low concentrations of ACh. Potentiation manifests as robust increases in the frequency of channel opening and the average duration of the openings. Molecular dynamics simulations reveal that calcium binds to the periphery of the five ligand binding sites and is framed by a pair of anionic residues from the principal and complementary faces of each site. Mutation of residues identified by simulation prevents calcium from potentiating ACh-elicited channel opening. An anionic residue is conserved at each of the identified positions in all vertebrate species of α7. Thus, calcium associates with a novel structural motif on α7 and is an obligate cofactor in regions of limited ACh concentration.

scholarly journals In Silico Finding of Key Interaction Mediated α3β4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype

2020 ◽  
Vol 21 (17) ◽  
pp. 6189
Author(s):  
Kuntarat Arunrungvichian ◽  
Sumet Chongruchiroj ◽  
Jiradanai Sarasamkan ◽  
Gerrit Schüürmann ◽  
Peter Brust ◽  
...  
Keyword(s):  
Amino Acid ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
In Silico ◽  
Amino Acid Residues ◽  
Nicotinic Acetylcholine ◽  
Selective Binding ◽  
Ligand Selectivity ◽  
Α7 Nachr ◽  
Nachr Subtype

The selective binding of six (S)-quinuclidine-triazoles and their (R)-enantiomers to nicotinic acetylcholine receptor (nAChR) subtypes α3β4 and α7, respectively, were analyzed by in silico docking to provide the insight into the molecular basis for the observed stereospecific subtype discrimination. Homology modeling followed by molecular docking and molecular dynamics (MD) simulations revealed that unique amino acid residues in the complementary subunits of the nAChR subtypes are involved in subtype-specific selectivity profiles. In the complementary β4-subunit of the α3β4 nAChR binding pocket, non-conserved AspB173 through a salt bridge was found to be the key determinant for the α3β4 selectivity of the quinuclidine-triazole chemotype, explaining the 47–327-fold affinity of the (S)-enantiomers as compared to their (R)-enantiomer counterparts. Regarding the α7 nAChR subtype, the amino acids promoting a however significantly lower preference for the (R)-enantiomers were the conserved TyrA93, TrpA149 and TrpB55 residues. The non-conserved amino acid residue in the complementary subunit of nAChR subtypes appeared to play a significant role for the nAChR subtype-selective binding, particularly at the heteropentameric subtype, whereas the conserved amino acid residues in both principal and complementary subunits are essential for ligand potency and efficacy.

scholarly journals Mechanism of interactions between α-conotoxin RegIIA and carbohydrates at the human α3β4 nicotinic acetylcholine receptor

2021 ◽  
Author(s):  
Meiling Zheng ◽  
Han-Shen Tae ◽  
Liang Xue ◽  
Tao Jiang ◽  
Rilei Yu
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Binding Sites ◽  
Chemical Properties ◽  
Binding Modes ◽  
Nicotinic Acetylcholine ◽  
Peptide Toxins ◽  
Dynamics Simulations ◽  
Relationship Of ◽  
Physical And Chemical

AbstractConotoxins are marine peptide toxins from marine cone snails. The α-conotoxin RegIIA can selectively act on human (h) α3β4 nicotinic acetylcholine receptor (nAChR), and is an important lead for drug development. The high-resolution cryo-electron microscopy structure of the α3β4 nAChR demonstrates several carbohydrates are located near the orthosteric binding sites, which may affect α-conotoxin binding. Oligosaccharide chains can modify the physical and chemical properties of proteins by changing the conformation, hydrophobicity, quality and size of the protein. The purpose of this study is to explore the effect of oligosaccharide chains on the binding modes and activities of RegIIA and its derivatives at hα3β4 nAChRs. Through computational simulations, we designed and synthesized RegIIA mutants at position 14 to explore the importance of residue H14 to the activity of the peptide. Molecular dynamics simulations suggest that the oligosaccharide chains affect the binding of RegIIA at the hα3β4 nAChR through direct interactions with H14 and by affecting the C-loop conformation of the binding sites. Electrophysiology studies on H14 analogues suggest that in addition to forming direct interactions with the carbohydrates, the residue might play an important role in maintaining the conformation of the peptide. Overall, this study further clarifies the structure–activity relationship of α-conotoxin RegIIA at the hα3β4 nAChR and, also provides important experimental and theoretical basis for the development of new peptide drugs.

scholarly journals The Impact of Electronic Nicotine Delivery System (ENDS) Flavors on Nicotinic Acetylcholine Receptors and Nicotine Addiction-Related Behaviors

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4223
Author(s):  
Skylar Y. Cooper ◽  
Brandon J. Henderson
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptors ◽  
Current Knowledge ◽  
Electronic Cigarettes ◽  
Nicotine Addiction ◽  
Receptor Subtypes ◽  
Primary Concern ◽  
Nicotinic Acetylcholine ◽  
The Impact

Over the past two decades, combustible cigarette smoking has slowly declined by nearly 11% in America; however, the use of electronic cigarettes has increased tremendously, including among adolescents. While nicotine is the main addictive component of tobacco products and a primary concern in electronic cigarettes, this is not the only constituent of concern. There is a growing market of flavored products and a growing use of zero-nicotine e-liquids among electronic cigarette users. Accordingly, there are few studies that examine the impact of flavors on health and behavior. Menthol has been studied most extensively due to its lone exception in combustible cigarettes. Thus, there is a broad understanding of the neurobiological effects that menthol plus nicotine has on the brain including enhancing nicotine reward, altering nicotinic acetylcholine receptor number and function, and altering midbrain neuron excitability. Although flavors other than menthol were banned from combustible cigarettes, over 15,000 flavorants are available for use in electronic cigarettes. This review seeks to summarize the current knowledge on nicotine addiction and the various brain regions and nicotinic acetylcholine receptor subtypes involved, as well as describe the most recent findings regarding menthol and green apple flavorants, and their roles in nicotine addiction and vaping-related behaviors.

Construction of cell line heterologously expressing the α6/3β2β3 nicotinic acetylcholine receptor (nAChR) subtype

2011 ◽  
Vol 82 (8) ◽  
pp. 1024-1025
Author(s):  
P. Whiteaker ◽  
L. Lucero ◽  
R.J. Lukas ◽  
C. Hepler ◽  
J.P. Strachan ◽  
...  
Keyword(s):  
Cell Line ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Nachr Subtype
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