scholarly journals From Crystal Structures of RgIA4 in Complex with Ac-AChBP to Molecular Determinants of Its High Potency of α9α10 nAChR

Marine Drugs ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. 709
Author(s):  
Si Pan ◽  
Yingxu Fan ◽  
Xiaopeng Zhu ◽  
Yi Xue ◽  
Sulan Luo ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Md Simulation ◽  
Selective Inhibitor ◽  
High Potency ◽  
Acetylcholine Binding Protein ◽  
Molecular Determinants ◽  
Key Residues ◽  
First Time

α9-containing nicotinic acetylcholine receptors (nAChRs) have been shown to play critical roles in neuropathic pain. The α-conotoxin (α-CTx) RgIA and its analog RgIA4 were identified as the most selective inhibitor of α9α10 nAChR. However, the mechanism of their selectivity toward α9α10 nAChR remains elusive. Here, we reported the co-crystal structure of RgIA and RgIA4 in complex with Aplysia californica acetylcholine binding protein (Ac-AChBP) at resolution of 2.6 Å, respectively. Based on the structure of the complexes, together with molecular dynamic simulation (MD-simulation), we suggested the key residues of α9α10 nAChR in determining its high affinity for RgIA/RgIA4. This is the first time the complex between pain-related conotoxins and Ac-AChBP was reported and the complementary side of α9 subunit in binding of the antagonists shown. These results provide realistic template for the design of new therapeutic in neuropathic pain.

scholarly journals Molecular Determinants for Competitive Inhibition of α4β2 Nicotinic Acetylcholine Receptors

2010 ◽  
Vol 78 (3) ◽  
pp. 366-375 ◽  
Author(s):  
Patricio Iturriaga-Vásquez ◽  
Annalisa Carbone ◽  
Olimpo García-Beltrán ◽  
Phil D. Livingstone ◽  
Philip C. Biggin ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Competitive Inhibition ◽  
Nicotinic Acetylcholine ◽  
Molecular Determinants

3-Furan-2-yl-N-p-tolyl-acrylamide, a highly selective positive allosteric modulator of α7 nicotinic receptors, produces anxiolytic-like activity in mice

2019 ◽  
Vol 33 (5) ◽  
pp. 558-567 ◽  
Author(s):  
Katarzyna M Targowska-Duda ◽  
Barbara Budzynska ◽  
Agnieszka Michalak ◽  
Krzysztof Jozwiak ◽  
Grazyna Biala ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Acute Treatment ◽  
Elevated Plus Maze ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Nicotinic Acetylcholine ◽  
Plus Maze ◽  
Α7 Nicotinic Acetylcholine Receptors ◽  
First Time

Background: Several lines of investigations support the idea that nicotinic acetylcholine receptors modulate neuronal pathways involved in anxiety and depression. Aims: The purpose of this study was to determine whether 3-furan-2-yl-N-p-tolyl-acrylamide, a highly selective positive allosteric modulator of α7 nicotinic acetylcholine receptors, influences anxiety-like behaviour in mice, and to determine the modulatory activity of 3-furan-2-yl-N-p-tolyl-acrylamide on mice pretreated with either nicotine or selective α7-agonists (i.e. PNU-282987 or (2.4)-dimethoxybenzylidene anabaseine dihydrochloride). Methods: The elevated plus maze and novelty suppressed feeding tests were selected to evaluate 3-furan-2-yl-N-p-tolyl-acrylamide and other nicotinic ligands on anxiety-like behaviour in mice. Results: The results indicated that: (a) 3-furan-2-yl-N-p-tolyl-acrylamide induces anxiolytic-like activity at 0.5 (elevated plus maze) and 1.0 (novelty suppressed feeding) mg/kg, respectively, after acute treatment, whereas its efficacy is increased after chronic treatments (i.e. active at 0.1 mg/kg; elevated plus maze). This is the first time showing anxiolytic-like activity elicited by 3-furan-2-yl-N-p-tolyl-acrylamide, contrary to the lack of activity for PNU-120596 (0.1 mg/kg); (b) the anxiolytic-like activity of 0.5 mg/kg 3-furan-2-yl-N-p-tolyl-acrylamide is inhibited by methyllycaconitine, a selective α7-antagonist, suggesting that α7 nicotinic acetylcholine receptors are involved in this process; (c) 0.5 mg/kg 3-furan-2-yl-N-p-tolyl-acrylamide reverses the anxiogenic effects induced by 0.1 mg/kg nicotine but not by 10.0 mg/kg PNU-282987; and (d) inactive doses of both 3-furan-2-yl-N-p-tolyl-acrylamide (0.1 mg/kg) and (2.4)-dimethoxybenzylidene anabaseine dihydrochloride (1.0 mg/kg) produce anxiolytic-like effects, suggesting drug interactions, probably synergistic. Conclusions: Our findings indicated that anxiolytic-like activity is mediated by α7 nicotinic acetylcholine receptors, supporting the concept that these receptors modulate anxiety processes. The results indicating that the chronic treatment with 3-furan-2-yl-N-p-tolyl-acrylamide is more efficient than the acute treatment in eliciting anxiolytic-like activity, and that 3-furan-2-yl-N-p-tolyl-acrylamide reverses the anxiogenic effects induced by nicotine, might be of therapeutic importance during smoking cessation.

scholarly journals Identification of Crucial Residues in α-Conotoxin EI Inhibiting Muscle Nicotinic Acetylcholine Receptor

Toxins ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 603 ◽  
Author(s):  
Jiong Ning ◽  
Jie Ren ◽  
Yang Xiong ◽  
Yong Wu ◽  
Manqi Zhangsun ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Fold Increase ◽  
Cd Spectroscopy ◽  
Xenopus Laevis Oocytes ◽  
Muscle Type ◽  
Nicotinic Acetylcholine ◽  
Activity Loss ◽  
Spectroscopy Studies ◽  
Key Residues

α-Conotoxins (α-CTxs) are small disulfide-rich peptides from venom of Conus species that target nicotinic acetylcholine receptors (nAChRs). The muscle-type nAChRs have been recognized as a potential target for several diseases, such as myogenic disorders, muscle dystrophies, and myasthenia gravis. EI, an α4/7-CTx, mainly blocks α1β1δε nAChRs and has an extra N-terminal extension of three amino acids. In this study, the alanine scanning (Ala-scan) mutagenesis was applied in order to identify key residues of EI for binding with mouse α1β1δε nAChR. The Ala-substituted analogues were tested for their abilities of modulating muscle and neuronal nAChRs in Xenopus laevis oocytes using two-electrode voltage clamp (TEVC) recordings. Electrophysiological results indicated that the vital residues for functional activity of EI were His-7, Pro-8, Met-12, and Pro-15. These changes exhibited a significant decrease in potency of EI against mouse α1β1δε nAChR. Interestingly, replacing the critical serine (Ser) at position 13 with an alanine (Ala) residue resulted in a 2-fold increase in potency at the α1β1δε nAChR, and showed loss of activity on α3β2 and α3β4 nAChRs. Selectivity and potency of [S13A] EI was improved compared with wild-type EI (WT EI). In addition, the structure–activity relationship (SAR) of EI revealed that the “Arg1–Asn2–Hyp3” residues at the N-terminus conferred potency at the muscle-type nAChRs, and the deletion analogue △1–3 EI caused a total loss of activity at the α1β1δε nAChR. Circular dichroism (CD) spectroscopy studies demonstrated that activity loss of truncated analogue △1–3 EI for α1β1δε nAChR is attributed to disturbance of the secondary structure. In this report, an Ala-scan mutagenesis strategy is presented to identify crucial residues that are significantly affecting potency of E1 for mouse α1β1δε nAChR. It may also be important in remodeling of some novel ligands for inhibiting muscle-type nAChRs.

Nicotinic acetylcholine receptors: α-conotoxins as templates for rational drug design

2003 ◽  
Vol 31 (3) ◽  
pp. 634-636 ◽  
Author(s):  
Robert W. Janes
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Structural Features ◽  
Docking Studies ◽  
Rational Drug Design ◽  
Synaptic Membranes ◽  
Nicotinic Acetylcholine ◽  
Computational Docking ◽  
Acetylcholine Binding Protein ◽  
Topological Features

Nicotinic acetylcholine receptors (nAChRs) mediate the passage of potassium and sodium ions across synaptic membranes. Two classes of receptors exist: the neuromuscular nAChRs, which mediate signals between nerve and muscle cells, and the neuronal nAChRs, which are found throughout the nervous system. For treatment of diseases involving nAChRs, drugs must be designed with a high level of selectivity towards only one of these classes or subclasses (in the case of neuronal receptors). α-Conotoxins, small polypeptides isolated from the venoms of marine snails, represent molecules with just this type of selectivity, with specificity even towards certain subclasses of nAChRs. The availability of high-resolution crystal structures of α-conotoxins provides the opportunity to examine the structural features that orchestrate their preferential blocking action. In the present study of a neuromuscular- and a neuronal-specific α-conotoxin, SI and EpI respectively, important and significant differences can be seen in the shapes of the molecules, which must reflect topological features of the different types of target receptor subunits. These then provide a template for computational docking studies with the homologous acetylcholine-binding protein, whose structure is known, so drug analogues of the naturally occurring toxins can be developed with the desired specificities.

scholarly journals RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats

Marine Drugs ◽  
2019 ◽  
Vol 18 (1) ◽  
pp. 12 ◽  
Author(s):  
Peter N. Huynh ◽  
Denise Giuvelis ◽  
Sean Christensen ◽  
Kerry L. Tucker ◽  
J. Michael McIntosh
Keyword(s):  
Neuropathic Pain ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Therapeutic Effects ◽  
Chemotherapeutic Drugs ◽  
Chemotherapeutic Drug ◽  
Sprague Dawley ◽  
Once Daily ◽  
Sprague Dawley Rats ◽  
Rescue Mechanism

Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus Conus for the treatment of neuropathic pain. α-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy resulting from the administration of oxaliplatin, a platinum-based antineoplastic drug. Here, we have examined its efficacy against paclitaxel, a chemotherapeutic drug that works by a mechanism of action distinct from that of oxaliplatin. Paclitaxel was administered at 2 mg/kg (intraperitoneally (IP)) every other day for a total of 8 mg/kg. Sprague Dawley rats that were co-administered RgIA4 at 80 µg/kg (subcutaneously (SC)) once daily, five times per week, for three weeks showed significant recovery from mechanical allodynia by day 31. Notably, the therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of α9α10 nicotinic acetylcholine receptors (nAChRs) as a non-opioid target in the treatment of chronic pain.

scholarly journals Coronaridine congeners decrease neuropathic pain in mice and inhibit α9α10 nicotinic acetylcholine receptors and CaV2.2 channels

2020 ◽  
Vol 175 ◽  
pp. 108194 ◽  
Author(s):  
Hugo R. Arias ◽  
Han-Shen Tae ◽  
Laura Micheli ◽  
Arsalan Yousuf ◽  
Carla Ghelardini ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine

scholarly journals Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

2017 ◽  
Vol 114 (10) ◽  
pp. E1825-E1832 ◽  
Author(s):  
Haylie K. Romero ◽  
Sean B. Christensen ◽  
Lorenzo Di Cesare Mannelli ◽  
Joanna Gajewiak ◽  
Renuka Ramachandra ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Underlying Mechanism ◽  
Nicotinic Acetylcholine ◽  
Cold Allodynia ◽  
Beneficial Effects ◽  
Oxaliplatin Treatment ◽  
Nonmalignant Pain

Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABABreceptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABABreceptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain.

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