Molecular mechanisms and binding site locations for noncompetitive antagonists of nicotinic acetylcholine receptors

2006 ◽  
Vol 38 (8) ◽  
pp. 1254-1276 ◽  
Author(s):  
Hugo R. Arias ◽  
Pankaj Bhumireddy ◽  
Cecilia Bouzat
Keyword(s):  
Binding Site ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Nicotinic Acetylcholine

Molecular Mechanisms and Binding Site Location for the Noncompetitive Antagonist Crystal Violet on Nicotinic Acetylcholine Receptors†

Biochemistry ◽  
2006 ◽  
Vol 45 (7) ◽  
pp. 2014-2026 ◽  
Author(s):  
Hugo R. Arias ◽  
Pankaj Bhumireddy ◽  
Guillermo Spitzmaul ◽  
James R. Trudell ◽  
Cecilia Bouzat
Keyword(s):  
Binding Site ◽  
Crystal Violet ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Site Location ◽  
Nicotinic Acetylcholine

scholarly journals Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

2020 ◽  
Vol 14 ◽  
Author(s):  
Thao N. T. Ho ◽  
Nikita Abraham ◽  
Richard J. Lewis
Keyword(s):  
Drug Design ◽  
Ligand Binding ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Rational Drug Design ◽  
Comprehensive Overview ◽  
Nicotinic Acetylcholine ◽  
Structure Based Drug Design ◽  
Selective Ligand

Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

scholarly journals Identifying the Binding Site of Novel Methyllycaconitine (MLA) Analogs at α4β2 Nicotinic Acetylcholine Receptors

2010 ◽  
Vol 1 (12) ◽  
pp. 796-809 ◽  
Author(s):  
Gracia X. J. Quek ◽  
Diana Lin ◽  
Jill I. Halliday ◽  
Nathan Absalom ◽  
Joseph I. Ambrus ◽  
...  
Keyword(s):  
Binding Site ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine

scholarly journals Nicotinic Acetylcholine Receptors as Potential Tumor Biomarkers in Genitourinary Cancers: a Review Study

2021 ◽  
Vol 1 (1) ◽  
pp. 4-4
Author(s):  
Khalil Hajiasgharzadeh ◽  
Behzad Baradaran ◽  
Leili Aghebati Maleki ◽  
Alireza Khabbazi
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Predictive Biomarkers ◽  
Relevant Information ◽  
Nicotinic Acetylcholine ◽  
Multiple Tumor ◽  
Review Study ◽  
Genitourinary Cancers

The genitourinary tissues express the different subtypes of nicotinic acetylcholine receptors (nAChRs), which are involved in many physiologic and pathologic processes. New studies have indicated the significant role of nAChRs in multiple tumor-related properties in different types of malignancies. Genitourinary cancers (GUCs) represent a heterogeneous population of cancers, in both histology and approach to treatment. nAChRs are functionally expressed by a variety of immune cells, tumor cells, and tumor-associated cells in the microenvironment of GUCs. In the current review study, publications until May 2021 were included in the literature review to summarize the potential effects and clinical and experimental significance of nAChRs in GUCs pathogenesis. The results yielded substantial and some paradoxical evidence regard the role of different subtypes of nAChRs as potential regulators and predictive biomarkers for GUCs. The accumulated evidence demonstrated that nAChRs levels were increased in the GUCs samples, which provides clinically relevant information on utilizing nAChRs as a new biomarker to improve the prognosis of these cancers. Also, activation or blockade of these receptors may lead to different downstream signaling pathways and cause diverse effects. Regarding the significant global burden of GUCs, evaluation of these receptors and delineating their molecular mechanisms could enrich our understanding of the biology of GUCs and may have new opportunities for clinical impacts.

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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