scholarly journals Pursuing High-Resolution Structures of Nicotinic Acetylcholine Receptors: Lessons Learned from Five Decades

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5753
Author(s):  
Manuel Delgado-Vélez ◽  
Orestes Quesada ◽  
Juan C. Villalobos-Santos ◽  
Rafael Maldonado-Hernández ◽  
Guillermo Asmar-Rovira ◽  
...  
Keyword(s):  
High Resolution ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Structural Features ◽  
Lessons Learned ◽  
Nicotinic Acetylcholine ◽  
Disease States ◽  
Pharmacological Targets ◽  
Therapeutic Value ◽  
Effective Drugs

Since their discovery, nicotinic acetylcholine receptors (nAChRs) have been extensively studied to understand their function, as well as the consequence of alterations leading to disease states. Importantly, these receptors represent pharmacological targets to treat a number of neurological and neurodegenerative disorders. Nevertheless, their therapeutic value has been limited by the absence of high-resolution structures that allow for the design of more specific and effective drugs. This article offers a comprehensive review of five decades of research pursuing high-resolution structures of nAChRs. We provide a historical perspective, from initial structural studies to the most recent X-ray and cryogenic electron microscopy (Cryo-EM) nAChR structures. We also discuss the most relevant structural features that emerged from these studies, as well as perspectives in the field.

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.

ShAR2β, a divergent nicotinic acetylcholine receptor subunit from the blood fluke Schistosoma

Parasitology ◽  
2007 ◽  
Vol 134 (6) ◽  
pp. 833-840 ◽  
Author(s):  
G. N. BENTLEY ◽  
A. K. JONES ◽  
A. AGNEW
Keyword(s):  
Amino Acid ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Transmembrane Domain ◽  
Structural Features ◽  
Amino Acid Residues ◽  
Nachr Subunit ◽  
Nicotinic Acetylcholine ◽  
Blood Fluke ◽  
Nematode Parasites

SUMMARYNicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that mediate the fast actions of the neurotransmitter, acetylcholine. Invertebrate nAChRs are of interest as they are targets of widely-selling insecticides and drugs that control nematode parasites. Here, we report the cloning of ShAR2β, a candidate nAChR subunit from the blood fluke, Schistosoma haematobium, which is the third trematode nAChR subunit to be characterized. While ShAR2β possesses key structural features common to all nAChRs, its amino acid sequence shares considerably low identity with those of insect, nematode and vertebrate nAChR subunits. In particular, the second transmembrane domain of ShAR2β, which lines the ion channel, bears unusual amino acid residues which will likely give rise to a receptor with distinct functional properties. Phylogenetic analysis shows that ShAR2β is a divergent nAChR subunit that may define a clade of trematode-specific subunits. We discuss our findings in the context of potentially exploiting this receptor as a target for controlling schistosome parasites.

Nicotinic acetylcholine receptors in the patients with Parkinson's disease: 5IA-SPECT

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S586-S586 ◽  
Author(s):  
Kazuo Hashikawa ◽  
Hidefumi Yoshida ◽  
Nobukatsu Sawamoto ◽  
Shigetoshi Takaya ◽  
Chihiro Namiki ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine
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