5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

2000 ◽  
Vol 57 (3) ◽  
pp. 642-649 ◽  
Author(s):  
Alexey G. Mukhin ◽  
Daniela Gündisch ◽  
Andrew G. Horti ◽  
Andrei O. Koren ◽  
Gilles Tamagnan ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine ◽  
Selective Ligand ◽  
Subtype Selective

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 Selective Ligand Behaviors Provide New Insights into Agonist Activation of Nicotinic Acetylcholine Receptors

2014 ◽  
Vol 9 (5) ◽  
pp. 1153-1159 ◽  
Author(s):  
Christopher B. Marotta ◽  
Iva Rreza ◽  
Henry A. Lester ◽  
Dennis A. Dougherty
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine ◽  
Selective Ligand

Localization of Nicotinic Acetylcholine Receptors on Somatic Spines of Chick Ciliary Ganglion Neurons

1999 ◽  
Vol 5 (S2) ◽  
pp. 1028-1029
Author(s):  
R. Shoop ◽  
M. Martone ◽  
N. Yamada ◽  
M. Ellisman ◽  
D. Berg
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Transmitter Release ◽  
Acetylcholine Receptors ◽  
Ciliary Ganglion ◽  
Nicotinic Acetylcholine ◽  
Selective Ligand ◽  
Somatic Spines ◽  
Ciliary Ganglion Neurons ◽  
Ganglion Neurons ◽  
Immunohistochemical Studies

Nicotinic acetylcholine receptors (nAChRs) are pentameric membrane proteins that function as cation selective, ligand-gated ion channels and are widely distributed throughout the vertebrate nervous system. One of the most abundant nAChRs is a species that contains the α7 gene product (α7-AChRs), binds the snake venom oc-bungarotoxin, and rapidly desensitizes. These receptors have been shown to function at presynaptic sites to modulate transmitter release, as well as on postsynaptic cells where they mediate transmission. Interestingly, these receptors have an exceptionally high relative permeability to calcium.In the chick ciliary ganglion, the α 7-AChRs play a prominent role, by generating large synaptic currents, but the receptors appear to be excluded from postysnaptic densities on the cell. Immunohistochemical studies have shown that the receptors form large clusters on the surface of the ciliary ganglion neurons. We have recently shown that the α 7-containing receptors are concentrated on mats of somatic spines in close proximity to putative sites of presynaptic transmitter release.

scholarly journals High-Throughput Patch Clamp Screening in Human α6-Containing Nicotinic Acetylcholine Receptors

2017 ◽  
Vol 22 (6) ◽  
pp. 686-695 ◽  
Author(s):  
Lucas C. Armstrong ◽  
Glenn E. Kirsch ◽  
Nikolai B. Fedorov ◽  
Caiyun Wu ◽  
Yuri A. Kuryshev ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Cell Line ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Brain Regions ◽  
Tobacco Product ◽  
Tobacco Products ◽  
Nicotinic Acetylcholine ◽  
Automated Patch Clamp ◽  
Subtype Selective

Nicotine, the addictive component of tobacco products, is an agonist at nicotinic acetylcholine receptors (nAChRs) in the brain. The subtypes of nAChR are defined by their α- and β-subunit composition. The α6β2β3 nAChR subtype is expressed in terminals of dopaminergic neurons that project to the nucleus accumbens and striatum and modulate dopamine release in brain regions involved in nicotine addiction. Although subtype-dependent selectivity of nicotine is well documented, subtype-selective profiles of other tobacco product constituents are largely unknown and could be essential for understanding the addiction-related neurological effects of tobacco products. We describe the development and validation of a recombinant cell line expressing human α6/3β2β3V273S nAChR for screening and profiling assays in an automated patch clamp platform (IonWorks Barracuda). The cell line was pharmacologically characterized by subtype-selective and nonselective reference agonists, pore blockers, and competitive antagonists. Agonist and antagonist effects detected by the automated patch clamp approach were comparable to those obtained by conventional electrophysiological assays. A pilot screen of a library of Food and Drug Administration–approved drugs identified compounds, previously not known to modulate nAChRs, which selectively inhibited the α6/3β2β3V273S subtype. These assays provide new tools for screening and subtype-selective profiling of compounds that act at α6β2β3 nicotinic receptors.

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