scholarly journals The allosteric activation of α7 nAChR by α-conotoxin MrIC is modified by mutations at the vestibular site

2021 ◽  
Author(s):  
Alican Gulsevin ◽  
Roger L Papke ◽  
Clare Stokes ◽  
Hue N. T. Tran ◽  
Ai-Hua Jin ◽  
...  
Keyword(s):  
Amino Acid ◽  
In Silico ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Allosteric Activation ◽  
Amino Acid Peptide ◽  
Α7 Nachr ◽  
Docking Calculations ◽  
Shed Light ◽  
Large Response

α-conotoxins are 13-19 amino acid toxin peptides that bind various nicotinic acetylcholine receptor (nAChR) subtypes. α-conotoxin Mr1.7c (MrIC) is a 17 amino acid peptide that targets α7 nAChR. Although MrIC has no activating effect on α7 nAChR when applied by itself, it evokes a large response when co-applied with the type II positive allosteric modulator PNU-120596, which potentiates α7 nAChR response by recovering it from a desensitized state. Lack of standalone activity despite activation upon co-application with a positive allosteric modulator was previously observed for molecules that bind to an extracellular domain allosteric activation (AA) site at the vestibule of the receptor. We hypothesized that MrIC may activate α7 nAChR allosterically through this site. We ran voltage-clamp electrophysiology experiments and in silico peptide docking calculations to gather evidence in support of α7 nAChR activation by MrIC through the AA site. The experiments with the wild-type α7 nAChR supported an allosteric mode of action, which was confirmed by the increased MrIC + PNU-120596 responses of three α7 nAChR AA site mutants that were designed in silico to improve MrIC binding. Overall, our results shed light on allosteric activation of α7 nAChR by MrIC and suggest involvement of the AA site.

In vitro and in vivo characterization of PheTQS, a novel α7 nAChR positive allosteric modulator

2009 ◽  
Vol 78 (7) ◽  
pp. 913 ◽  
Author(s):  
James N.C. Kew ◽  
Selina Mok ◽  
Annette Weil ◽  
Caterina Virginio ◽  
Laura Castelletti ◽  
...  
Keyword(s):  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Α7 Nachr ◽  
In Vivo Characterization

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 In silico Investigation of Curcumin as a Positive Allosteric Modulator of a7‐Nicotinic Acetylcholine Receptors

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Tatiana Prytkova ◽  
Mirue Kang ◽  
Tri Ngoc Quang Tran ◽  
Jiwoo You ◽  
Younji Jeong ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
In Silico ◽  
Acetylcholine Receptors ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Nicotinic Acetylcholine

scholarly journals Docking Studies of Binding of Ethambutol to the C-Terminal Domain of the Arabinosyltransferase fromMycobacterium tuberculosis

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Guillermo Salgado-Moran ◽  
Rodrigo Ramirez-Tagle ◽  
Daniel Glossman-Mitnik ◽  
Samuel Ruiz-Nieto ◽  
Pran Kishore-Deb ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Amino Acid ◽  
In Silico ◽  
Docking Studies ◽  
Stable Complex ◽  
Amino Acid Residues ◽  
Terminal Domain ◽  
Docking Calculations

The binding of ethambutol to the C-terminal domain of the arabinosyltransferase fromMycobacterium tuberculosiswas studied. The analysis was performed using anin silicoapproach in order to find out, by docking calculations and energy descriptors, the conformer of Ethambutol that forms the most stable complex with the C-terminal domain of arabinosyltransferase. The complex shows that location of the Ethambutol coincides with the cocrystallization ligand position and that amino acid residues ASH1051, ASN740, ASP1052, and ARG1055 should be critical in the binding of Ethambutol to C-terminal domain EmbC.

APN0417: A potent and efficacious α7 nAChR positive allosteric modulator

2015 ◽  
Vol 97 (4) ◽  
pp. 636
Author(s):  
Olivier Dasse ◽  
Geoffrey Bilcer ◽  
David Putman ◽  
Raymond Ng ◽  
Kelvin Gee ◽  
...  
Keyword(s):  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Α7 Nachr

Effects of α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator on BDNF, NKCC1 and KCC2 Expression in the Hippocampus following Lipopolysaccharide-induced Allodynia and Hyperalgesia in a Mouse Model of Inflammatory Pain

2020 ◽  
Vol 19 ◽  
Author(s):  
Muzaffar Abbas ◽  
Sami Alzarea ◽  
Roger L Papke ◽  
Shafiqur Rahman
Keyword(s):  
Mouse Model ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Inflammatory Pain ◽  
Neuronal Excitability ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Α7 Nachr

Background & Objective: Hyperalgesia and allodynia are frequent symptoms of inflammatory pain. Neuronal excitability induced by brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) cascade has a role in the modulation of inflammatory pain. The effects of 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline8-sulfonamide (TQS), an α7 nicotinic acetylcholine receptor positive allosteric modulator (nAChR PAM), on hippocampal BDNF, cation-chloride cotransporters, NKCC1 and KCC2, expression in inflammatory pain are not known. The objective of the study was to determine the effects of TQS on BDNF, NKCC1, and KCC2 expression in the hippocampus following lipopolysaccharide (LPS)-induced allodynia and hyperalgesia in a mouse model of inflammatory pain. Methods: Mice were treated with TQS followed by LPS (1 mg/kg, ip) administration. The effects of TQS on mRNA and BDNF in the hippocampus were examined using qRT-PCR and Western blot, respectively. Immunoreactivity of BDNF, NKCC1, and KCC2 in the hippocampus was measured after LPS administration using immunofluorescence assay. Allodynia and hyperalgesia were determined using von Frey filaments and hot plate, respectively. Results: The LPS (1 mg/kg) upregulates mRNA of BDNF and downregulates mRNA of KCC2 in the hippocampus and pretreatment of TQS (4 mg/kg) reversed the effects induced by LPS. In addition, the TQS decreased LPS-induced upregulation of BDNF and p-NKCC1 immunoreactivity in dentate gyrus and CA1 region of the hippocampus. BDNF receptor (TrkB) antagonist, ANA12 (0.50 mg/kg), and NKCC1 inhibitor bumetanide (30 mg/kg) reduced LPS-induced allodynia and hyperalgesia. Blockade of TrkB with ANA12 (0.25 mg/kg) enhanced the effects of TQS (1 mg/kg) against LPS-induced allodynia and hyperalgesia. Similarly, bumetanide (10 mg/kg) enhanced the effects of TQS (1 mg/kg) against allodynia and hyperalgesia. Conclusion: These results suggest that antinociceptive effects of α7 nAChR PAM are associated with downregulation of hippocampal BDNF and p-NKCC1 and upregulation of KCC2 in a mouse model of inflammatory pain.

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